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Intellectual disability v3.1495 CSNK2B Sarah Leigh Added comment: Comment on phenotypes: Intellectual disability with or without myoclonic epilepsy
Intellectual disability v3.1495 CSNK2B Sarah Leigh Phenotypes for gene: CSNK2B were changed from Intellectual disability with or without myoclonic epilepsy to Poirier-Bienvenu neurodevelopmental syndrome, OMIM:618732; Poirier-Bienvenu neurodevelopmental syndrome, MONDO:0032889
Intellectual disability v3.1494 CSNK2B Sarah Leigh Publications for gene: CSNK2B were set to 28585349; 28762608; 30655572
Intellectual disability v3.1493 XPNPEP3 Sarah Leigh reviewed gene: XPNPEP3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1493 XPNPEP3 Sarah Leigh Publications for gene: XPNPEP3 were set to 20179356
Intellectual disability v3.1492 XPNPEP3 Sarah Leigh Phenotypes for gene: XPNPEP3 were changed from Nephronophthisis-like nephropathy 1, 613159 to Nephronophthisis-like nephropathy 1 OMIM:613159; nephronophthisis-like nephropathy 1 MONDO:0013163
Intellectual disability v3.1491 SPATA5L1 Ivone Leong Classified gene: SPATA5L1 as Amber List (moderate evidence)
Intellectual disability v3.1491 SPATA5L1 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 and Gene2Phenotype (limited). There is enough evidence to support a gene-disease association, this gene should be rated Green.
Intellectual disability v3.1491 SPATA5L1 Ivone Leong Gene: spata5l1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1490 SPATA5L1 Ivone Leong Tag Q1_22_rating tag was added to gene: SPATA5L1.
Intellectual disability v3.1490 SPATA5L1 Ivone Leong Phenotypes for gene: SPATA5L1 were changed from Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616 to Neurodevelopmental disorder with hearing loss and spasticity, OMIM:619616
Intellectual disability v3.1489 PSMB8 Arina Puzriakova Phenotypes for gene: PSMB8 were changed from Autoinflammation, lipodystrophy, and dermatosis syndrome, 256040 to Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040
Intellectual disability v3.1488 OTULIN Arina Puzriakova Phenotypes for gene: OTULIN were changed from Otulin-related auto inflammatory syndrome (ORAS) to Autoinflammation, panniculitis, and dermatosis syndrome, OMIM:617099
Intellectual disability v3.1487 NLRP3 Arina Puzriakova Phenotypes for gene: NLRP3 were changed from Cold-induced autoinflammatory syndrome, familial, 120100Muckle-Wells syndrome, 191900CINCA syndrome, 607115 to CINCA syndrome, OMIM:607115
Intellectual disability v3.1486 MVK Arina Puzriakova Phenotypes for gene: MVK were changed from Mevalonic aciduria to Mevalonic aciduria, OMIM:610377
Intellectual disability v3.1485 MYO5B Arina Puzriakova Phenotypes for gene: MYO5B were changed from Microvillus inclusion disease, 251850 to Diarrhea 2, with microvillus atrophy, OMIM:251850
Intellectual disability v3.1484 HEXB Arina Puzriakova Phenotypes for gene: HEXB were changed from Sandhoff disease, infantile, juvenile, and adult forms, 268800; GM2-GANGLIOSIDOSIS TYPE 2 (GM2G2) to Sandhoff disease, infantile, juvenile, and adult forms, OMIM:268800
Intellectual disability v3.1483 ATAD1 Ivone Leong Phenotypes for gene: ATAD1 were changed from Hyperekplexia 4, MIM#618011 to Hyperekplexia 4, OMIM:618011
Intellectual disability v3.1482 ATAD1 Ivone Leong Publications for gene: ATAD1 were set to 28180185
Intellectual disability v3.1481 KCND2 Eleanor Williams Classified gene: KCND2 as Amber List (moderate evidence)
Intellectual disability v3.1481 KCND2 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a recommendation for green rating following GMS review. 3 cases reported with missense variants in this gene with no seizures, plus further cases with seizures.
Intellectual disability v3.1481 KCND2 Eleanor Williams Gene: kcnd2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1480 KCND2 Eleanor Williams Tag Q4_21_rating tag was added to gene: KCND2.
Intellectual disability v3.1480 KCND2 Eleanor Williams gene: KCND2 was added
gene: KCND2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCND2 were set to 34245260; 16934482; 24501278
Phenotypes for gene: KCND2 were set to global developmental delay, HP:0001263
Mode of pathogenicity for gene: KCND2 was set to Other
Added comment: 6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype.

PMID:16934482 - Singh et al, 2006 - reports a patient with cognitive impairment who also went on to have seizures starting from age 13 with a 5 bp deletion in KCND2 leading to premature stop codon. The proband's asymptomatic father also shared this variant.

Also:
PMID:24501278 - Lee et al, 2014 - reports pair of monozygotic twin boys with infantile onset severe refractory epilepsy and autism. A de novo heterozygous missense variant was identified by WES - V404M.
Sources: Literature
Intellectual disability v3.1479 GNB5 Arina Puzriakova Phenotypes for gene: GNB5 were changed from Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182; Intellectual developmental disorder with cardiac arrhythmia, 617173 to Intellectual developmental disorder with cardiac arrhythmia, OMIM:617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, OMIM:617182
Intellectual disability v3.1478 NSRP1 Zornitza Stark gene: NSRP1 was added
gene: NSRP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to Epilepsy; Cerebral palsy; microcephaly; Intellectual disability
Review for gene: NSRP1 was set to GREEN
gene: NSRP1 was marked as current diagnostic
Added comment: Novel gene regulating splicing. Biallelic LoF pathogenic variants reported in 6 individuals from 3 unrelated families associated with a phenotype characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.
Sources: Literature
Intellectual disability v3.1478 SPRED2 Zornitza Stark gene: SPRED2 was added
gene: SPRED2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRED2 were set to 34626534
Phenotypes for gene: SPRED2 were set to developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt
Review for gene: SPRED2 was set to GREEN
gene: SPRED2 was marked as current diagnostic
Added comment: PMID: 34626534
Homozygosity for three different variants c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95) were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behaviour. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome.
Sources: Literature
Intellectual disability v3.1478 SPATA5L1 Zornitza Stark gene: SPATA5L1 was added
gene: SPATA5L1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPATA5L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5L1 were set to 34626583
Phenotypes for gene: SPATA5L1 were set to Neurodevelopmental disorder with hearing loss and spasticity, MIM# 619616
Review for gene: SPATA5L1 was set to GREEN
gene: SPATA5L1 was marked as current diagnostic
Added comment: 47 individuals from 26 unrelated families from various ethnicities with biallelic variants reported. Phenotypes include ID, hearing impairment, movement disorder, abnormal MRI, hypotonia, visual impairment, epilepsy, and microcephaly.

~53% of patients had ID.
Sources: Literature
Intellectual disability v3.1478 OGDHL Zornitza Stark gene: OGDHL was added
gene: OGDHL was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 34800363
Phenotypes for gene: OGDHL were set to Neurodevelopmental disorder featuring epilepsy, hearing loss and visual impairment
Review for gene: OGDHL was set to GREEN
Added comment: Nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing
loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum.

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

Functional studies with a CRISPR-Cas9-mediated tissue knockout with cDNA rescue system showed that the missense variants result in loss-of-function.
Sources: Literature
Intellectual disability v3.1478 FOXR1 Zornitza Stark gene: FOXR1 was added
gene: FOXR1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FOXR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXR1 were set to 34723967
Phenotypes for gene: FOXR1 were set to Postnatal microcephaly, progressive brain atrophy and global developmental delay
Review for gene: FOXR1 was set to AMBER
Added comment: 1 patient described with a de novo missense variant. Phenotypes include: postnatal microcephaly, progressive brain atrophy, skeletal abnormalities, brain abnormalities, ophthalmic abnormalities, neuromuscular abnormalities, and dysmorphic features. A variant in ATP1A3 was considered to have contributed to the final phenotype.

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

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

Rated amber (1 patient, functional evidence, mouse model).
Sources: Literature
Intellectual disability v3.1478 RNPC3 Ivone Leong changed review comment from: PMID:33650182 a third case reported with growth failure and ID. This is the second case where a patient with a variant in RNPC3 has ID. Therefore the Amber rating.; to: PMID:33650182 a third case reported with growth failure. This is the second case where a patient with a variant in RNPC3 has ID. Therefore the Amber rating.
Intellectual disability v3.1478 RNPC3 Ivone Leong changed review comment from: PMID:33650182 a third case reported with growth failure and ID.; to: PMID:33650182 a third case reported with growth failure and ID. This is the second case where a patient with a variant in RNPC3 has ID. Therefore the Amber rating.
Intellectual disability v3.1478 RNPC3 Ivone Leong changed review comment from: Comment on list classification: Promoted from Red to Amber based on my other review.; to: Comment on list classification: Promoted from Red to Amber based on my other review.
Intellectual disability v3.1478 RNPC3 Ivone Leong Tag watchlist tag was added to gene: RNPC3.
Intellectual disability v3.1478 RNPC3 Ivone Leong Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814
Intellectual disability v3.1477 RNPC3 Ivone Leong Phenotypes for gene: RNPC3 were changed from isolated growth hormone deficiency; ?Growth hormone deficiency, isolated, type V, 618160; developmental delay/intellectual deficiency and delayed puberty to Pituitary hormone deficiency, combined or isolated, 7, OMIM:618160
Intellectual disability v3.1476 RNPC3 Ivone Leong Classified gene: RNPC3 as Amber List (moderate evidence)
Intellectual disability v3.1476 RNPC3 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on my other review.
Intellectual disability v3.1476 RNPC3 Ivone Leong Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1475 RNPC3 Ivone Leong edited their review of gene: RNPC3: Added comment: PMID:33650182 a third case reported with growth failure and ID.; Changed rating: AMBER; Changed publications to: 24480542, 29866761, 32462814, 33650182
Intellectual disability v3.1475 ANK3 Dmitrijs Rots reviewed gene: ANK3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34218362; Phenotypes: Intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1475 HMGB1 Dmitrijs Rots reviewed gene: HMGB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1475 PHF6 Ivone Leong reviewed gene: PHF6: Rating: ; Mode of pathogenicity: None; Publications: 24092917, 25099957; 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 v3.1475 PHF6 Ivone Leong Phenotypes for gene: PHF6 were changed from Borjeson-Forssman-Lehmann syndrome, 301900; BOERJESON-FORSSMAN-LEHMANN SYNDROME (BFLS) to Borjeson-Forssman-Lehmann syndrome, OMIM:301900
Intellectual disability v3.1474 PHF6 Ivone Leong Publications for gene: PHF6 were set to
Intellectual disability v3.1473 PHF6 Ivone Leong Tag Q4_21_MOI tag was added to gene: PHF6.
Intellectual disability v3.1473 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181; AICARDI-GOUTIERES SYNDROME 2 to Aicardi-Goutieres syndrome 2, OMIM:610181
Intellectual disability v3.1472 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from Martsolf syndrome, 212720Warburg micro syndrome 2, 614225; MARTSOLF SYNDROME (MARTS) to Martsolf syndrome 1, OMIM:212720; Warburg micro syndrome 2, OMIM:614225
Intellectual disability v3.1471 MAPK8IP3 Arina Puzriakova Phenotypes for gene: MAPK8IP3 were changed from Abnormal muscle tone; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Neurodevelopmental disorder with or without variable brain abnormalities, 618443 to Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443
Intellectual disability v3.1470 IFIH1 Arina Puzriakova Phenotypes for gene: IFIH1 were changed from AICARDI-GOUTIERES SYNDROME 7 to Aicardi-Goutieres syndrome 7, OMIM:615846
Intellectual disability v3.1469 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from Multiple mitochondrial dysfunctions syndrome 3, 615330; intellectual disability, seizures, loss of milestones to Multiple mitochondrial dysfunctions syndrome 3, OMIM:615330
Intellectual disability v3.1468 GPT2 Arina Puzriakova Phenotypes for gene: GPT2 were changed from Microcephaly; Mental retardation, autosomal recessive 49, 138210; Intellectual disability; Progressive spasticity to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Intellectual disability v3.1467 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057; 34764295
Intellectual disability v3.1466 EXOSC3 Arina Puzriakova Phenotypes for gene: EXOSC3 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 1 to Pontocerebellar hypoplasia, type 1B, OMIM:614678
Intellectual disability v3.1465 ATP9A Sarah Leigh edited their review of gene: ATP9A: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants reported in four unrelated families with a neurodevelopmental disorder (PMIDs: 34379057, 34764295). Model Atp9a−/− mice had neurobehavioural disabilities reminiscent to the behavioral patterns in the publications quoted here (PMID: 27626380).; Changed rating: GREEN; Changed publications to: 27626380
Intellectual disability v3.1465 ATP9A Sarah Leigh Classified gene: ATP9A as Amber List (moderate evidence)
Intellectual disability v3.1465 ATP9A 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 v3.1465 ATP9A Sarah Leigh Gene: atp9a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1464 ATP9A Sarah Leigh Tag Q4_21_rating tag was added to gene: ATP9A.
Intellectual disability v3.1464 ATP9A Sarah Leigh Publications for gene: ATP9A were set to 34379057
Intellectual disability v3.1463 HCCS Ivone Leong Tag Q4_21_MOI tag was added to gene: HCCS.
Intellectual disability v3.1463 HCCS Ivone Leong reviewed gene: HCCS: Rating: ; Mode of pathogenicity: None; Publications: ; 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 v3.1463 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic paraplegia 48, autosomal recessive 613647 to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Intellectual disability v3.1462 HPRT1 Arina Puzriakova Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, 300322HPRT-related gout, 300323; GOUT HPRT-RELATED (GOUT-HPRT) to Lesch-Nyhan syndrome, OMIM:300322
Intellectual disability v3.1461 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity, 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity OMIM:617296
Intellectual disability v3.1460 KIDINS220 Arina Puzriakova Publications for gene: KIDINS220 were set to 27005418; 29667355
Intellectual disability v3.1459 CARS Arina Puzriakova Phenotypes for gene: CARS were changed from Brittle hair; Fragile nails; Microcephaly; Neurodevelopmental delay; Microcephaly, developmental delay, and brittle hair syndrome MIM#618891 to Microcephaly, developmental delay, and brittle hair syndrome, OMIM:618891
Intellectual disability v3.1458 GABRD Arina Puzriakova Classified gene: GABRD as Amber List (moderate evidence)
Intellectual disability v3.1458 GABRD Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases to rate this gene as Green at the next GMS panel update. Although all patients presented epilepsy, it is not clear from the case reports whether cognitive impairment was secondary or independent of seizures. For this reason I think its worth including GABRD on this panel as it is plausible that DD may be evident prior to seizure onset (ranging from 4 months to 4 years in report)
Intellectual disability v3.1458 GABRD Arina Puzriakova Gene: gabrd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1457 GABRD Arina Puzriakova gene: GABRD was added
gene: GABRD was added to Intellectual disability. Sources: Literature
Q4_21_rating tags were added to gene: GABRD.
Mode of inheritance for gene: GABRD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRD were set to 34633442
Phenotypes for gene: GABRD were set to {Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060
Mode of pathogenicity for gene: GABRD 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: GABRD was set to GREEN
Added comment: Ahring et al., 2021 (PMID: 34633442) reports on at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene. All variants exerted a gain-of-function effect and all carriers displayed a homogenous phenotype of generalised epilepsy (median age of onset 10.5 months, medically refractory in 5/6) and various degrees of learning difficulties or ID (learning difficulties in 1, mild ID in 2, mild to moderate ID in 1, and severe to profound ID in 2).

NB. A further three individuals were excluded from phenotypic analysis as their variants (p.M87L and p.V442I) did not show any detectable functional changes. There was also another patient with a loss-of-function variant but they displayed ASD, normal intelligence and no seizure history.
Sources: Literature
Intellectual disability v3.1456 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25597510
Intellectual disability v3.1455 CLPB Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update.

Association between biallelic variants and disease is well established, with more than 35 affected individuals reported. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease, including mild to severe DD/ID in all cases. Some functional studies of heterozygous variants were performed.
Intellectual disability v3.1455 CLPB Arina Puzriakova Mode of inheritance for gene: CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1454 CLPB Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLPB.
Intellectual disability v3.1454 AR Arina Puzriakova Phenotypes for gene: AR were changed from Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300; Hypospadias 1, X-linked, OMIM:300633; Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Intellectual disability v3.1453 FXN Arina Puzriakova Phenotypes for gene: FXN were changed from Friedreich ataxia 229300; Friedreich ataxia with retained reflexes 229300 to Friedreich ataxia, OMIM:229300; Friedreich ataxia with retained reflexes, OMIM:229300
Intellectual disability v3.1452 GLS_GCA Arina Puzriakova Phenotypes for STR: GLS_GCA were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
Intellectual disability v3.1451 GLS Arina Puzriakova commented on gene: GLS: Added 'watchlist_MOI' tag to highlight monoallelic phenotype (MIM# 618339) which is also relevant to this panel, but as there is only a single case reported to date this is not yet sufficient to update the MOI.
Intellectual disability v3.1451 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Intellectual disability v3.1450 GLS Arina Puzriakova Tag watchlist_moi tag was added to gene: GLS.
Intellectual disability v3.1450 NOP56 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1450 NOP56 Arina Puzriakova Mode of inheritance for gene: NOP56 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1449 NOP56 Arina Puzriakova Phenotypes for gene: NOP56 were changed from Spinocerebellar ataxia 36, 614153 to Spinocerebellar ataxia 36, OMIM:614153
Intellectual disability v3.1448 NOP56 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: NOP56.
Tag currently-ngs-unreportable tag was added to gene: NOP56.
Intellectual disability v3.1448 PPP2R2B Arina Puzriakova Mode of pathogenicity for gene: PPP2R2B 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 v3.1447 PPP2R2B Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1447 PPP2R2B Arina Puzriakova Mode of inheritance for gene: PPP2R2B was changed from Other - please specify in evaluation comments to Other
Intellectual disability v3.1446 PPP2R2B Arina Puzriakova Phenotypes for gene: PPP2R2B were changed from Spinocerebellar ataxia 12, 604326 to Spinocerebellar ataxia 12, OMIM:604326
Intellectual disability v3.1445 PPP2R2B Arina Puzriakova Tag watchlist was removed from gene: PPP2R2B.
Intellectual disability v3.1445 PPP2R2B_CAG Arina Puzriakova Phenotypes for STR: PPP2R2B_CAG were changed from Spinocerebellar ataxia 12 604326 to Spinocerebellar ataxia 12, OMIM:604326
Intellectual disability v3.1444 TBP Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1444 TBP Arina Puzriakova Mode of inheritance for gene: TBP was changed from Other - please specify in evaluation comments to Other
Intellectual disability v3.1443 TBP Arina Puzriakova Mode of pathogenicity for gene: TBP 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 v3.1442 TBP Arina Puzriakova Phenotypes for gene: TBP were changed from Spinocerebellar ataxia 17, 607136; {Parkinson disease, susceptibility to}, 168600 to Spinocerebellar ataxia 17, OMIM:607136
Intellectual disability v3.1441 TBP Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: TBP.
Tag currently-ngs-unreportable tag was added to gene: TBP.
Intellectual disability v3.1441 HTT Arina Puzriakova Publications for gene: HTT were set to 26740508; 27329733
Intellectual disability v3.1440 HTT Arina Puzriakova Phenotypes for gene: HTT were changed from Lopes-Maciel-Rodan syndrome, 617435; LOMARS; Intellectual disability to Lopes-Maciel-Rodan syndrome, OMIM:617435; LOMARS
Intellectual disability v3.1439 FMR1_CGG Arina Puzriakova Phenotypes for STR: FMR1_CGG were changed from Fragile X syndrome 300624 to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Intellectual disability v3.1438 FMR1_CGG Arina Puzriakova Tag currently-ngs-unreportable was removed from STR: FMR1_CGG.
Intellectual disability v3.1438 FMR1 Arina Puzriakova Phenotypes for gene: FMR1 were changed from Fragile X syndrome, 300624Fragile X tremor/ataxia syndrome, 300623Premature ovarian failure 1, 311360; PREMATURE OVARIAN FAILURE SYNDROME TYPE 1 (POF1) to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
Intellectual disability v3.1437 FMR1 Arina Puzriakova Tag currently-ngs-unreportable was removed from gene: FMR1.
Intellectual disability v3.1437 ATXN1 Arina Puzriakova Phenotypes for gene: ATXN1 were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Intellectual disability v3.1436 ATXN1 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1436 ATXN1 Arina Puzriakova Mode of inheritance for gene: ATXN1 was changed from BIALLELIC, autosomal or pseudoautosomal to Other
Intellectual disability v3.1435 ATXN1_CAG Arina Puzriakova Phenotypes for STR: ATXN1_CAG were changed from Spinocerebellar ataxia 1 164400 to Spinocerebellar ataxia 1, OMIM:164400
Intellectual disability v3.1434 JPH3 Arina Puzriakova Phenotypes for gene: JPH3 were changed from Intellectual disability; dystonia to Neurodevelopmental disorder, MONDO:0700092; Paroxysmal dystonia, MONDO:0016058
Intellectual disability v3.1433 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1 160900 to Myotonic dystrophy 1, OMIM:160900
Intellectual disability v3.1432 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1, 160900; DYSTROPHIA MYOTONICA TYPE 1 (DM1) to Myotonic dystrophy 1, OMIM:160900
Intellectual disability v3.1431 DMPK Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1431 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1430 CSTB Arina Puzriakova Phenotypes for gene: CSTB were changed from UNVERRICHT-LUNDBORG DISEASE to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Intellectual disability v3.1429 CSTB_CCCCGCCCCGCG Arina Puzriakova Phenotypes for STR: CSTB_CCCCGCCCCGCG were changed from Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800 to Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), OMIM:254800
Intellectual disability v3.1428 FARSA Ivone Leong Tag Q4_21_rating tag was added to gene: FARSA.
Intellectual disability v3.1428 FARSA Ivone Leong Classified gene: FARSA as Amber List (moderate evidence)
Intellectual disability v3.1428 FARSA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. There is now enough evidence to support a gene-disease association (>3 cases). This gene should be rated Green at the next review.
Intellectual disability v3.1428 FARSA Ivone Leong Gene: farsa has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1427 CACNA1A Arina Puzriakova Phenotypes for gene: CACNA1A were changed from Epileptic encephalopathy, early infantile, 42 617106; Episodic ataxia, type 2 108500; Migraine, familial hemiplegic, 1 141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia 141500; Spinocerebellar ataxia 6 183086 to Developemental and epileptic encephalopathy 42, OMIM:617106
Intellectual disability v3.1426 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Intellectual disability v3.1425 C9orf72 Arina Puzriakova Mode of pathogenicity for gene: C9orf72 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 v3.1424 C9orf72 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1424 C9orf72 Arina Puzriakova Mode of inheritance for gene: C9orf72 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1423 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Intellectual disability v3.1422 ATXN7_CAG Arina Puzriakova Phenotypes for STR: ATXN7_CAG were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Intellectual disability v3.1421 ATXN7 Arina Puzriakova Phenotypes for gene: ATXN7 were changed from Spinocerebellar ataxia 7 164500 to Spinocerebellar ataxia 7, OMIM:164500
Intellectual disability v3.1420 ATXN7 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1420 ATXN7 Arina Puzriakova Mode of inheritance for gene: ATXN7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1419 ATXN3_CAG Arina Puzriakova Phenotypes for STR: ATXN3_CAG were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Intellectual disability v3.1418 ATXN3 Arina Puzriakova Mode of pathogenicity for gene: ATXN3 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 v3.1417 ATXN3 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1417 ATXN3 Arina Puzriakova Mode of inheritance for gene: ATXN3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1416 ATXN3 Arina Puzriakova Phenotypes for gene: ATXN3 were changed from Machado-Joseph disease 109150 to Machado-Joseph disease, OMIM:109150
Intellectual disability v3.1415 ATXN3 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN3.
Intellectual disability v3.1415 ATXN2_CAG Arina Puzriakova Phenotypes for STR: ATXN2_CAG were changed from Spinocerebellar ataxia 2 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Intellectual disability v3.1414 ATXN2 Arina Puzriakova Mode of pathogenicity for gene: ATXN2 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 v3.1413 ATXN2 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1413 ATXN2 Arina Puzriakova Mode of inheritance for gene: ATXN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1412 ATXN2 Arina Puzriakova Phenotypes for gene: ATXN2 were changed from Spinocerebellar ataxia 2 183090; {Amyotrophic lateral sclerosis, susceptibility to, 13} 183090 to Spinocerebellar ataxia 2, OMIM:183090; {Amyotrophic lateral sclerosis, susceptibility to, 13}, OMIM:183090; {Parkinson disease, late-onset, susceptibility to}, OMIM:168600
Intellectual disability v3.1411 ATXN2 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN2.
Intellectual disability v3.1411 ATXN10_ATTCT Arina Puzriakova Phenotypes for STR: ATXN10_ATTCT were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Intellectual disability v3.1410 ATXN10 Arina Puzriakova Added comment: Comment on mode of inheritance: Lack of phenotypic relevance for SNVs - nucleotide repeat expansion mechanism
Intellectual disability v3.1410 ATXN10 Arina Puzriakova Mode of inheritance for gene: ATXN10 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Other
Intellectual disability v3.1409 ATXN10 Arina Puzriakova Phenotypes for gene: ATXN10 were changed from Spinocerebellar ataxia 10 603516 to Spinocerebellar ataxia 10, OMIM:603516
Intellectual disability v3.1408 ATN1 Arina Puzriakova Publications for gene: ATN1 were set to 24972706; 30827498
Intellectual disability v3.1407 ATN1 Arina Puzriakova 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 Congenital hypotonia, epilepsy, developmental delay, and digital anomalies, OMIM:618494
Intellectual disability v3.1406 KIDINS220 Dmitrijs Rots reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33763417; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1406 VAMP7 Ivone Leong Tag Pseudoautosomal region 2 tag was added to gene: VAMP7.
Intellectual disability v3.1406 SPRY3 Ivone Leong Tag Pseudoautosomal region 2 tag was added to gene: SPRY3.
Intellectual disability v3.1406 SLC25A6 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SLC25A6.
Intellectual disability v3.1406 SHOX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: SHOX.
Intellectual disability v3.1406 PLCXD1 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: PLCXD1.
Intellectual disability v3.1406 P2RY8 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: P2RY8.
Intellectual disability v3.1406 IL3RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: IL3RA.
Intellectual disability v3.1406 DHRSX Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: DHRSX.
Intellectual disability v3.1406 CSF2RA Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CSF2RA.
Intellectual disability v3.1406 CRLF2 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CRLF2.
Intellectual disability v3.1406 CD99 Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: CD99.
Intellectual disability v3.1406 ASMTL Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: ASMTL.
Intellectual disability v3.1406 ASMT Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: ASMT.
Intellectual disability v3.1406 AKAP17A Ivone Leong Tag Pseudoautosomal region 1 tag was added to gene: AKAP17A.
Intellectual disability v3.1406 NUP85 Eleanor Williams Classified gene: NUP85 as Amber List (moderate evidence)
Intellectual disability v3.1406 NUP85 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 2 cases reported but degree of ID not confirmed in the second family.
Intellectual disability v3.1406 NUP85 Eleanor Williams Gene: nup85 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1405 NUP85 Eleanor Williams changed review comment from: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from the 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro), which segregated from the maternal and the paternal side.
Sources: Literature; to: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction.

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro) in NUP85.
Sources: Literature
Intellectual disability v3.1405 NUP85 Eleanor Williams gene: NUP85 was added
gene: NUP85 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NUP85 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP85 were set to 34170319
Phenotypes for gene: NUP85 were set to Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS)
Review for gene: NUP85 was set to AMBER
Added comment: PMID: 34170319 - Ravindran et al 2021 report two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS. In the first family, a 9 yo female, with consanguineous parents, is reported to have a missense variant in NUP85 (c.932G > A; p.R311Q). Intrauterine growth restriction was noticed. At birth microcephaly was observed (OFC < 3rd centile, < −3.6 SD) as well as hypotrophy [weight −2.8 SD), length 45 cm (−2.7 SD), both <3rd centile], facial dysmorphism, syndactyly, long and thin fingers, and bilateral pes adductus. She has severe developmental delay with strongly delayed motor milestones and absent speech. Drug-resistant, genetic epilepsy with focal-onset seizures started in the first year of life. She had no clinical, laboratory or radiological findings indicative of kidney dysfunction

In the second family, compound heterozygous missense variants in NUP85 were detected
(c.1109A > G, c.1589 T > C;p.N370S, p.M530T ) in a fetus. MRI of the fetal brain at 24 + 2 GW indicated complete agenesis of the corpus callosum, abnormal sulcation in the left frontal lobe, nodularity of the frontal horn and trigone with focal puckering of the left lateral ventricle.

PMID: 30179222 - Braun et al 2018 - 2 individuals from the 1 of the families reported with steroid-resistant nephrotic syndrome were also reported to have intellectual disability but showed no structural brain defects. The degree of intellectual disability is not stated. They were found to have 2 compound heterozygous alleles (c.405+1G>A and c.1741G>C, p.Ala581Pro), which segregated from the maternal and the paternal side.
Sources: Literature
Intellectual disability v3.1404 SLC6A9 Arina Puzriakova Phenotypes for gene: SLC6A9 were changed from Glycine encephalopathy with normal serum glycine, 617301; Glycine encephalopathy and global developmental delay to Glycine encephalopathy with normal serum glycine, OMIM:617301
Intellectual disability v3.1403 CLPB Ivone Leong Phenotypes for gene: CLPB were changed from 3-METHYLGLUTACONIC ACIDURIA, TYPE VII, WITH CATARACTS, NEUROLOGIC INVOLVEMENT AND NEUTROPENIA to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Intellectual disability v3.1402 LMNB2 Arina Puzriakova Phenotypes for gene: LMNB2 were changed from Congenital microcephaly; Global developmental delay; Intellectual disability to Microcephaly 27, primary, autosomal dominant, OMIM:619180
Intellectual disability v3.1401 LMNB1 Arina Puzriakova 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; LMNB1-associated developmental disorder to Microcephaly 26, primary, autosomal dominant, OMIM:619179
Intellectual disability v3.1400 EXTL3 Arina Puzriakova Phenotypes for gene: EXTL3 were changed from Immunoskeletal dysplasia with neurodevelopmental abnormalities 617425 to Immunoskeletal dysplasia with neurodevelopmental abnormalities, OMIM:617425
Intellectual disability v3.1399 EIF5A Arina Puzriakova Phenotypes for gene: EIF5A were changed from Intellectual disability; microcephaly; dysmorphism to Faundes-Banka syndrome, OMIM:619376
Intellectual disability v3.1398 CDK8 Arina Puzriakova 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; Intellectual developmental disorder with hypotonia and behavioral abnormalities #618748 to Intellectual developmental disorder with hypotonia and behavioral abnormalities, OMIM:618748
Intellectual disability v3.1397 ERCC6 Ivone Leong Added comment: Comment on phenotypes: Previous phenotype entry:
Cockayne syndrome, type B, 133540Cerebrooculofacioskeletal syndrome 1, 214150De Sanctis-Cacchione syndrome, 278800{Macular degeneration, age-related, susceptibility to 5}, 613761UV-sensitive syndrome 1, 600630{Lung cancer, susceptibility to}, 211980;DE SANCTIS-CACCHIONE SYNDROME (DSC)
Intellectual disability v3.1397 ERCC6 Ivone Leong Phenotypes for gene: ERCC6 were changed from Cockayne syndrome, type B, 133540Cerebrooculofacioskeletal syndrome 1, 214150De Sanctis-Cacchione syndrome, 278800{Macular degeneration, age-related, susceptibility to 5}, 613761UV-sensitive syndrome 1, 600630{Lung cancer, susceptibility to}, 211980; DE SANCTIS-CACCHIONE SYNDROME (DSC) to De Sanctis-Cacchione syndrome, OMIM:278800
Intellectual disability v3.1396 RAP1GDS1 Dmitrijs Rots changed review comment from: Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846; to: Additional cases (three with same splice variant, which segregates in one family) and one frameshift variant reported in PMID: 33875846. Cases seem to overlap those reported in PMID: 32431071.
Intellectual disability v3.1396 RAP1GDS1 Dmitrijs Rots reviewed gene: RAP1GDS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846; Phenotypes: Intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1396 PLK1 Dmitrijs Rots gene: PLK1 was added
gene: PLK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK1 were set to PMID: 33875846
Phenotypes for gene: PLK1 were set to Epilepsy; microcephaly; intellectual disability
Review for gene: PLK1 was set to GREEN
Added comment: >5 cases with epileptic encephalopathy with homozygous variants in PMID: 33875846
Sources: Literature
Intellectual disability v3.1396 RAB11A Dmitrijs Rots reviewed gene: RAB11A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33875846, 26902202; Phenotypes: microcephaly, brain anomalies, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1396 SNIP1 Sarah Leigh commented on gene: SNIP1: Q4_21_expert_review tag has been added to this gene. Helen Brittain (Genomics England Clinical Fellow) has suggested that the rating of this gene should be considered by TEWG oversight committee, to decide whether this gene could be green, as the disease association has only been associated with a the founder variant.
Intellectual disability v3.1396 SNIP1 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: SNIP1.
Intellectual disability v3.1396 DHDDS Arina Puzriakova Publications for gene: DHDDS were set to 29100083; 27343064
Intellectual disability v3.1395 DHDDS Arina Puzriakova Tag Q4_21_MOI tag was added to gene: DHDDS.
Intellectual disability v3.1395 DHDDS Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Both mono- and biallelic' to 'Monoallelic' at the next GMS panel update. Monoallelic variants are associated with a neurodevelopmental disorder comprising DD/ID, epilepsy and a variable movement disorder phenotype - >3 unrelated individuals reported in literature. To date, only one individual with biallelic variants and ID has been reported (PMID: 27343064). This patient presented with glycosylation defects but no corroborating cases have been reported since.
As only one patient has been described with biallelic inheritance and this phenotype, MOI should be set to 'Monoallelic' until evidence of additional cases emerges - biallelic variants would still be picked up by the Genomics England pipeline under this MOI.
Intellectual disability v3.1395 DHDDS Arina Puzriakova 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 v3.1394 DHDDS Arina Puzriakova Phenotypes for gene: DHDDS were changed from Developmental delay and seizures with or without movement abnormalities, 617836; ?Congenital disorder of glycosylation, type 1bb, 613861 to Developmental delay and seizures with or without movement abnormalities, OMIM:617836
Intellectual disability v3.1393 CRYBB3 Arina Puzriakova Phenotypes for gene: CRYBB3 were changed from Cataract 22, autosomal recessive, 609741 to Cataract 22, OMIM:609741
Intellectual disability v3.1392 CRYBB3 Arina Puzriakova Mode of inheritance for gene: CRYBB3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1391 COL9A3 Arina Puzriakova Phenotypes for gene: COL9A3 were changed from Epiphyseal dysplasia, multiple, 3, 600969; Epiphyseal dysplasia, multiple, with myopathy; {Intervertebral disc disease, susceptibility to}, 603932 to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969
Intellectual disability v3.1390 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Intellectual disability v3.1389 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Intellectual disability v3.1389 COL9A2 Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Epiphyseal dysplasia, multiple, 2, 600204; {Intervertebral; disc disease, susceptibility to}, 603932; ?Stickler syndrome, type V, 614284 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204
Intellectual disability v3.1388 COL9A1 Arina Puzriakova Phenotypes for gene: COL9A1 were changed from ?Epiphyseal dysplasia, multiple, 6, 614135; Stickler syndrome, type IV, 614134 to Stickler syndrome, type IV, OMIM:614134; Epiphyseal dysplasia, multiple, 6, OMIM:614135
Intellectual disability v3.1387 COL6A3 Arina Puzriakova Mode of inheritance for gene: COL6A3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1386 COL6A3 Arina Puzriakova Phenotypes for gene: COL6A3 were changed from Gene2Phenotype confirmed gene with ID HPO to Bethlem myopathy, OMIM:158810; Ullrich congenital muscular dystrophy, OMIM:254090
Intellectual disability v3.1385 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Intellectual disability v3.1384 COL6A1 Arina Puzriakova Mode of inheritance for gene: COL6A1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1383 COL4A4 Arina Puzriakova Mode of inheritance for gene: COL4A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1382 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Alport syndrome, autosomal recessive, 203780; Hematuria, familial benign to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Intellectual disability v3.1381 CLPB Dmitrijs Rots reviewed gene: CLPB: 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: PMID: 34140661; Phenotypes: Neutropenia, intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1381 CDH15 Arina Puzriakova Tag Q4_21_rating tag was added to gene: CDH15.
Intellectual disability v3.1381 CDH15 Arina Puzriakova Classified gene: CDH15 as Green List (high evidence)
Intellectual disability v3.1381 CDH15 Arina Puzriakova Added comment: Comment on list classification: Gene should be demoted to Red as there is limited evidence supporting this gene-disease association. The only cases reported to date with SNVs were discovered by targeted sequencing of CDH15. Clinical information was limited, describing only mild ID in some cases. There are also multiple benign LOF variants in population databases. Asymptomatic carriers lead authors to suggest incomplete penetrance but all identified variants are in gnomAD so are unlikely to be causal.
Intellectual disability v3.1381 CDH15 Arina Puzriakova Gene: cdh15 has been classified as Green List (High Evidence).
Intellectual disability v3.1380 CDH15 Arina Puzriakova Publications for gene: CDH15 were set to
Intellectual disability v3.1379 CDH15 Arina Puzriakova Phenotypes for gene: CDH15 were changed from Mental retardation, autosomal dominant 3, 612580; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 3 (MRD3) to Mental retardation, autosomal dominant 3, OMIM:612580
Intellectual disability v3.1378 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4, 611490; Osteopetrosis, autosomal dominant 2, 166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Intellectual disability v3.1377 CLCN7 Arina Puzriakova Mode of inheritance for gene: CLCN7 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1376 BLOC1S1 Ivone Leong Tag watchlist tag was added to gene: BLOC1S1.
Intellectual disability v3.1376 ARFGEF1 Ivone Leong Phenotypes for gene: ARFGEF1 were changed from Intellectual disability; Epilepsy to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Classified gene: ARFGEF1 as Amber List (moderate evidence)
Intellectual disability v3.1375 ARFGEF1 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 (probable) but not in OMIM. There are >3 unrelated cases. ID in patients ranged from mild to moderate, which does not satisfy the criteria for this panel (moderate to severe); however, as this is one of the presenting features this gene has will be recommended to be Green at the next review.
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Gene: arfgef1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1374 ARFGEF1 Ivone Leong Tag Q4_21_rating tag was added to gene: ARFGEF1.
Intellectual disability v3.1374 PRDM12 Sarah Leigh Mode of inheritance for gene: PRDM12 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1373 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from NA to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Intellectual disability v3.1372 PRDM12 Sarah Leigh Publications for gene: PRDM12 were set to
Intellectual disability v3.1371 ZC4H2 Ivone Leong reviewed gene: ZC4H2: Rating: ; Mode of pathogenicity: None; Publications: ; 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 v3.1371 ZC4H2 Ivone Leong Tag Q4_21_MOI tag was added to gene: ZC4H2.
Intellectual disability v3.1371 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from ARTHROGRYPOSIS MULTIPLEX CONGENITA AND INTELLECTUAL DISABILITY to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Intellectual disability v3.1370 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to
Intellectual disability v3.1369 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.
Intellectual disability v3.1369 AP1S2 Arina Puzriakova Mode of inheritance for gene: AP1S2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1368 AP1S2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: AP1S2.
Intellectual disability v3.1368 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic, Fried type, 300630; MENTAL RETARDATION X-LINKED TYPE 59 (MRX59) to Pettigrew syndrome, OMIM:304340
Intellectual disability v3.1367 BLOC1S1 Dmitrijs Rots gene: BLOC1S1 was added
gene: BLOC1S1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to PMID: 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Review for gene: BLOC1S1 was set to GREEN
Added comment: 4 cases with similar phenotype and inheritance reported
Sources: Literature
Intellectual disability v3.1367 FAAH2 Dmitrijs Rots reviewed gene: FAAH2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34645488; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1367 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Biallelic' only. Mild cognitive impairment has been reported in some patients with CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ID. There is also controversy regarding any link between CLCN2 and epilepsy.
Intellectual disability v3.1367 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1366 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to Leukoencephalopathy with ataxia, OMIM:615651
Intellectual disability v3.1365 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 23707145; 19191339
Intellectual disability v3.1364 ZDHHC15 Ivone Leong Added comment: Comment on phenotypes: Previously associated with ?Mental retardation, X-linked 91, OMIM:300577; however, OMIM has removed this
Intellectual disability v3.1364 ZDHHC15 Ivone Leong Phenotypes for gene: ZDHHC15 were changed from ?Mental retardation, X-linked 91, 300577 to cerebral palsy; intellectual disability; autism spectrum disorder; epilepsy
Intellectual disability v3.1363 ZDHHC15 Ivone Leong Added comment: Comment on publications: New publication added PMID:34345675
Intellectual disability v3.1363 ZDHHC15 Ivone Leong Publications for gene: ZDHHC15 were set to 15915161
Intellectual disability v3.1362 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Intellectual disability v3.1362 RAD51 Arina Puzriakova Added comment: Comment on list classification: Intellectual disability has been reported in 2/3 individuals with RAD51-associated FA (third patient with mild early DD). However, a syndromic presentation prior to this is expected. Potential for VUSs in pure ID cohort, although there is an allied chromosome breakage test. Upgrading from Red to Amber - which also reflects the rating of other FA genes associated with ID.
Intellectual disability v3.1362 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1361 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Mirror movements 2, OMIM:614508 to Fanconi anemia, complementation group R, OMIM:617244
Intellectual disability v3.1360 RAD51 Arina Puzriakova Publications for gene: RAD51 were set to 22305526; 21242494
Intellectual disability v3.1359 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1359 ABHD16A Ivone Leong Tag Q4_21_rating tag was added to gene: ABHD16A.
Intellectual disability v3.1359 ABHD16A Ivone Leong Classified gene: ABHD16A as Amber List (moderate evidence)
Intellectual disability v3.1359 ABHD16A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1359 ABHD16A Ivone Leong Gene: abhd16a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1358 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Mirror movements 2,614508 to Mirror movements 2, OMIM:614508
Intellectual disability v3.1357 DDX23 Ivone Leong Publications for gene: DDX23 were set to 33057194
Intellectual disability v3.1356 SARS Ivone Leong Classified gene: SARS as Amber List (moderate evidence)
Intellectual disability v3.1356 SARS 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 and Gene2Phenotype. As there are only 2 cases there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1356 SARS Ivone Leong Gene: sars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1355 SARS Ivone Leong Tag watchlist tag was added to gene: SARS.
Intellectual disability v3.1355 SARS Ivone Leong commented on gene: SARS
Intellectual disability v3.1355 SARS Ivone Leong Tag new-gene-name tag was added to gene: SARS.
Intellectual disability v3.1355 SARS Ivone Leong Phenotypes for gene: SARS were changed from Intellectual disability to ?Neurodevelopmental disorder with microcephaly, ataxia, and seizures, OMIM:617709
Intellectual disability v3.1354 ATP6V0C Ivone Leong Classified gene: ATP6V0C as Amber List (moderate evidence)
Intellectual disability v3.1354 ATP6V0C Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1354 ATP6V0C Ivone Leong Gene: atp6v0c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1353 ATP6V0C Ivone Leong Tag watchlist tag was added to gene: ATP6V0C.
Intellectual disability v3.1353 ATP11A Ivone Leong Tag watchlist tag was added to gene: ATP11A.
Intellectual disability v3.1353 ATP11A Ivone Leong Classified gene: ATP11A as Amber List (moderate evidence)
Intellectual disability v3.1353 ATP11A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently only 1 case and a mouse model which showed neurological deficit phenotypes (including tremors, abnormal gait, hind limb clasping and reduction in brain size. The patient was a 26 yo male born to healthy non-consanguineous Japanese parents. At birth his length was -3.3. SD and OFC was -1.3 SD. Developed epilepsy at 2 weeks followed by global developmental delay and mild hypothyroidism and cataracts.He suffered gradual lost of developmental milestones. At 18 yo, height was -4.6 SD and OFC was -4.0 SD.

As there is currently not enough evidence to support a gene-disease association, this gene has been given an Amber rating.
Intellectual disability v3.1353 ATP11A Ivone Leong Gene: atp11a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1352 SNIP1 Sarah Leigh Classified gene: SNIP1 as Amber List (moderate evidence)
Intellectual disability v3.1352 SNIP1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease.
Intellectual disability v3.1352 SNIP1 Sarah Leigh Gene: snip1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1351 SNIP1 Sarah Leigh Publications for gene: SNIP1 were set to 22279524
Intellectual disability v3.1350 SNIP1 Sarah Leigh Tag founder-effect tag was added to gene: SNIP1.
Intellectual disability v3.1350 SNIP1 Sarah Leigh Phenotypes for gene: SNIP1 were changed from Psychomotor retardation, epilepsy, and craniofacial dysmorphism, 614501; severe developmental delay to Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501; psychomotor retardation, epilepsy, and craniofacial dysmorphism MONDO:0013787
Intellectual disability v3.1349 KIRREL3 Ivone Leong Added comment: Comment on publications: New publication added (PMID:33853164)
Intellectual disability v3.1349 KIRREL3 Ivone Leong Publications for gene: KIRREL3 were set to 22965935; 19012874
Intellectual disability v3.1348 WDR11 Ivone Leong Classified gene: WDR11 as Amber List (moderate evidence)
Intellectual disability v3.1348 WDR11 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in Gene2Phenotype (probable) but not in OMIM. There is enough evidence to support a gene-disease association; however, the severity of ID in the patients described in PMID:34413497 does not fit the criteria for this panel (panel is for moderate to severe ID, patients have mild ID). Therefore, this gene has been given an Amber rating.

The OFC of patients in PMID: 34413497 ranged from -3.09 SD to -4.93 SD)
Intellectual disability v3.1348 WDR11 Ivone Leong Gene: wdr11 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1347 WDR11 Ivone Leong Added comment: Comment on phenotypes: Previously associated with Kallmann syndrome.
Intellectual disability v3.1347 WDR11 Ivone Leong Phenotypes for gene: WDR11 were changed from KALLMANN SYNDROME to Intellectual disability, MONDO:0001071; Microcephaly, MONDO:0001149; Short stature,HP:0004322
Intellectual disability v3.1346 WDR11 Ivone Leong Publications for gene: WDR11 were set to 26350204
Intellectual disability v3.1345 WDR11 Ivone Leong Added comment: Comment on mode of inheritance: Changed MOI from "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown" to "BIALLELIC, autosomal or pseudoautosomal" as biallelic variants in this gene is associated with ID.
Intellectual disability v3.1345 WDR11 Ivone Leong Mode of inheritance for gene: WDR11 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1344 WDR11 Ivone Leong Tag watchlist tag was added to gene: WDR11.
Intellectual disability v3.1344 PRICKLE2 Ivone Leong Phenotypes for gene: PRICKLE2 were changed from Epilepsy, progressive myoclonic 5, 613832 to Neurodevelopmental disorder; global developmental delay
Intellectual disability v3.1344 PRICKLE2 Ivone Leong Publications for gene: PRICKLE2 were set to
Intellectual disability v3.1343 PRICKLE2 Ivone Leong Tag Q4_21_rating tag was added to gene: PRICKLE2.
Intellectual disability v3.1343 PRICKLE2 Ivone Leong Classified gene: PRICKLE2 as Amber List (moderate evidence)
Intellectual disability v3.1343 PRICKLE2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently enough evidence to support a gene-disease association. Therefore this gene should be rated Green at the next review.
Intellectual disability v3.1343 PRICKLE2 Ivone Leong Gene: prickle2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1342 GRIK2 Ivone Leong Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant to Mental retardation, autosomal recessive, 6, OMIM:611092; non-syndromic neurodevelopmental disorder (NDD), autosomal dominant
Intellectual disability v3.1341 GRIK2 Ivone Leong Tag Q4_21_MOI tag was added to gene: GRIK2.
Intellectual disability v3.1341 GRIK2 Ivone Leong reviewed gene: GRIK2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1341 GRIK2 Ivone Leong Publications for gene: GRIK2 were set to
Intellectual disability v3.1340 GRIK2 Ivone Leong Phenotypes for gene: GRIK2 were changed from Mental retardation, autosomal recessive, 6, 611092; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 6 (MRT6) to Mental retardation, autosomal recessive, 6, OMIM:611092; on-syndromic neurodevelopmental disorder (NDD), autosomal dominant
Intellectual disability v3.1339 CACNA1I Ivone Leong Classified gene: CACNA1I as Amber List (moderate evidence)
Intellectual disability v3.1339 CACNA1I Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype 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 v3.1339 CACNA1I Ivone Leong Gene: cacna1i has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1338 CACNA1I Ivone Leong Tag Q4_21_rating tag was added to gene: CACNA1I.
Intellectual disability v3.1338 SHANK1 Zornitza Stark reviewed gene: SHANK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34113010, 22503632, 25188300; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1338 PLXNA1 Zornitza Stark gene: PLXNA1 was added
gene: PLXNA1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PLXNA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PLXNA1 were set to 34054129
Phenotypes for gene: PLXNA1 were set to Neurodevelopmental disorder with cerebral and eye anomalies
Review for gene: PLXNA1 was set to GREEN
Added comment: Dworschak et al. (2021) via WES reported 10 patients from 7 families with biallelic (n=7) or de novo (n=3) PLXNA1 variants. Shared phenotypic features include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Seizures were predominantly reported in patients with monoallelic variants. Zebrafish studies showed an embryonic role of plxna1a in the development of the central nervous system and the eye. Biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
Sources: Literature
Intellectual disability v3.1338 CHRM1 Ivone Leong Tag watchlist tag was added to gene: CHRM1.
Intellectual disability v3.1338 CHRM1 Ivone Leong Deleted their comment
Intellectual disability v3.1338 HNRNPD Zornitza Stark edited their review of gene: HNRNPD: Added comment: More individuals reported in PMID 33874999; Changed rating: GREEN; Changed publications to: 33057194, 33874999; Changed phenotypes to: Developmental disorders, Intellectual disability
Intellectual disability v3.1338 CHRM1 Ivone Leong Classified gene: CHRM1 as Amber List (moderate evidence)
Intellectual disability v3.1338 CHRM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently not enough evidence to support a gene-disease association this gene has been given an Amber rating.
Intellectual disability v3.1338 CHRM1 Ivone Leong Gene: chrm1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1338 CHRM1 Ivone Leong Classified gene: CHRM1 as Amber List (moderate evidence)
Intellectual disability v3.1338 CHRM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently not enough evidence to support a gene-disease association this gene has been given an Amber rating.
Intellectual disability v3.1338 CHRM1 Ivone Leong Gene: chrm1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1337 CHRM1 Ivone Leong Phenotypes for gene: CHRM1 were changed from Neurodevelopmental delay; intellectual disability; autism to Neurodevelopmental delay; intellectual disability, MONDO:0001071; autism
Intellectual disability v3.1336 SARS Zornitza Stark gene: SARS was added
gene: SARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to Intellectual disability
Review for gene: SARS was set to AMBER
Added comment: Summary - 2 unrelated families with overlapping ID phenotype, and supporting in vitro and patient cell assays.

PMID: 28236339 - an Iranian family (distantly related) segregating a homozygous missense (c.514G>A, p.Asp172Asn) with moderate ID, microcephaly, ataxia, speech impairment, and aggressive behaviour. Also, supporting in vitro functional assays demonstrating altered protein function.
PMID: 34570399 - a consanguineous Turkish family segregating a homozygous missense (c.638G>T, p.(Arg213Leu)) with developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death. Also, reduced protein level and enzymatic activity in patient cells.
Sources: Literature
Intellectual disability v3.1336 ZNF699 Ivone Leong Tag Q4_21_rating tag was added to gene: ZNF699.
Intellectual disability v3.1336 ZNF699 Ivone Leong Classified gene: ZNF699 as Amber List (moderate evidence)
Intellectual disability v3.1336 ZNF699 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 but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1336 ZNF699 Ivone Leong Gene: znf699 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1335 ZDHHC15 Zornitza Stark reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: 34345675; Phenotypes: Mental retardation, X-linked 91, 300577, cerebral palsy, intellectual disability, autism spectrum disorder, epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1335 ATP11A Zornitza Stark gene: ATP11A was added
gene: ATP11A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to 34403372
Phenotypes for gene: ATP11A were set to Neurodevelopmental disorder
Review for gene: ATP11A was set to AMBER
Added comment: PMID: 34403372:
- Single de novo missense variant reported in a patient with developmental delay and neurological deterioration.
- Patient MRI showed severe cerebral atrophy, ventriculomegaly, hypomyelination leukodystrophy, thinned corpus callosum. Axonal neuropathy suggested.
- K/I heterozygous mice died perinatally.
- Functional studies on missense variant show plasma membrane lipid content impairment, reduced ATPase activity etc.

gnomAD: some NMD PTCs present, good quality variants found with 4-5 hets.
Sources: Literature
Intellectual disability v3.1335 ZNF699 Ivone Leong Phenotypes for gene: ZNF699 were changed from DEGCAGS syndrome, MIM# 619488 to DEGCAGS syndrome, OMIM:619488
Intellectual disability v3.1334 ABHD16A Zornitza Stark gene: ABHD16A was added
gene: ABHD16A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Review for gene: ABHD16A was set to GREEN
gene: ABHD16A was marked as current diagnostic
Added comment: 11 individuals from 6 families with a complicated form of hereditary spastic paraplegia who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
In 5 of the families the affected members were homozygous, 3 of these families were consanguineous. 2 families have the same variant- both families are French-Canadian.
4 missense variants, 1 frameshift, 1 nonsense.
Sources: Literature
Intellectual disability v3.1334 JAKMIP1 Ivone Leong Tag watchlist tag was added to gene: JAKMIP1.
Intellectual disability v3.1334 JAKMIP1 Ivone Leong Classified gene: JAKMIP1 as Amber List (moderate evidence)
Intellectual disability v3.1334 JAKMIP1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Currently there are only 2 cases; however, there is very little information about the two cases in the papers. Therefore, this gene has been given an Amber rating until more evidence is available.
Intellectual disability v3.1334 JAKMIP1 Ivone Leong Gene: jakmip1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1333 JAKMIP1 Ivone Leong Phenotypes for gene: JAKMIP1 were changed from Intellectual disability; seizures to Intellectual disability, MONDO:0001071; seizures
Intellectual disability v3.1332 ATP6V0C Zornitza Stark gene: ATP6V0C was added
gene: ATP6V0C was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP6V0C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V0C were set to 33190975; 33090716
Phenotypes for gene: ATP6V0C were set to Epilepsy; Intellectual Disability; microcephaly
Review for gene: ATP6V0C was set to AMBER
Added comment: 9 individuals reported with deletions and ID/seizures/microcephaly, minimum overlapping region implicates ATP6V0C as the causative gene. Single case report of de novo SNV and ID/seizures.
Sources: Literature
Intellectual disability v3.1332 ARFGEF1 Zornitza Stark gene: ARFGEF1 was added
gene: ARFGEF1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ARFGEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF1 were set to 34113008
Phenotypes for gene: ARFGEF1 were set to Intellectual disability; Epilepsy
Review for gene: ARFGEF1 was set to GREEN
Added comment: 13 individuals reported with variants in this gene and a neurodevelopmental disorder characterised by variable ID, seizures present in around half. Variants were inherited from mildly affected parents in 40% of families.
Sources: Literature
Intellectual disability v3.1332 KIF4A Zornitza Stark reviewed gene: KIF4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 24812067, 34346154; Phenotypes: Mental retardation, X-linked 100, MIM# 300923; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1332 TAF2 Zornitza Stark reviewed gene: TAF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34474177, 21937992, 22633631, 26350204; Phenotypes: Mental retardation, autosomal recessive 40, OMIM # 615599; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1332 DDX23 Zornitza Stark edited their review of gene: DDX23: Added comment: PMID 34050707: 9 unrelated individuals (gathered through GeneMatcher) with de novo missense alterations in DDX23. Clinical features include: tone abnormalities, global developmental delay, facial dysmorphism, autism spectrum disorder, and seizures. Additionally, there were a variety of other findings in the skeletal, renal, ocular, and cardiac systems. The missense alterations all occurred within a highly conserved RecA-like domain of the protein, and are located within or proximal to the DEAD box sequence. The gene is ubiquitously expressed and functions in RNA splicing, maintenance of genome stability, and the sensing of double-stranded RNA.; Changed rating: GREEN; Changed publications to: 33057194, 34050707
Intellectual disability v3.1332 HMGB1 Zornitza Stark gene: HMGB1 was added
gene: HMGB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HMGB1 were set to 34164801
Phenotypes for gene: HMGB1 were set to Developmental delay and microcephaly
Review for gene: HMGB1 was set to GREEN
gene: HMGB1 was marked as current diagnostic
Added comment: 13q12.3 microdeletion syndrome is a rare cause of syndromic ID. Previous studies identified four genes within the ~300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1.

Uguen et al. (2021) report 6 patients with LOF variants involving HMGB1 with features similar to 13q12.3 microdeletion syndrome (i.e. developmental delay, language delay, microcephaly, obesity and dysmorphic features). In silico analyses suggest that HMGB1 is likely to be intolerant to LOF, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. They suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.
Sources: Literature
Intellectual disability v3.1332 WIPI2 Zornitza Stark edited their review of gene: WIPI2: Added comment: PMID: 34557665 (2021)
- two novel homozygous variants were identified in four individuals of two consanguineous families.
- one family presented with microcephaly, profound global developmental delay/intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures and dyskinesia.
- second family (similar to initial publication) presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait.
- functional studies showed dysregulation of the early steps of the autophagy pathway.; Changed rating: GREEN; Changed publications to: 30968111, 34557665; Set current diagnostic: yes
Intellectual disability v3.1332 ZNF668 Ivone Leong Tag watchlist tag was added to gene: ZNF668.
Intellectual disability v3.1332 ZNF668 Ivone Leong Classified gene: ZNF668 as Amber List (moderate evidence)
Intellectual disability v3.1332 ZNF668 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is currently no phenotypes associated with this gene in OMIM or Gene2Phenotype. As there are only 2 cases there is currently not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Intellectual disability v3.1332 ZNF668 Ivone Leong Gene: znf668 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1331 UBE2U Ivone Leong Classified gene: UBE2U as Red List (low evidence)
Intellectual disability v3.1331 UBE2U Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a disease in Gene2Phenotype (there is currently no entry for this gene in OMIM). As there is currently only 1 case this gene has been given a Red rating.
Intellectual disability v3.1331 UBE2U Ivone Leong Gene: ube2u has been classified as Red List (Low Evidence).
Intellectual disability v3.1330 UBE2U Ivone Leong Phenotypes for gene: UBE2U were changed from Retinoschisis; cataracts; learning disabilities; developmental delay to Retinoschisis, MONDO:0004579; cataracts; learning disability, MONDO:0004681; developmental delay
Intellectual disability v3.1329 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum to Intellectual disability, MONDO:0001071
Intellectual disability v3.1328 RNF220 Ivone Leong Classified gene: RNF220 as Amber List (moderate evidence)
Intellectual disability v3.1328 RNF220 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association; however, the ID severity in these patients do not meet the criteria (moderate to severe) for this panel (patients show mild (mostly) to moderate severity). Therefore, this gene has been given an Amber rating.
Intellectual disability v3.1328 RNF220 Ivone Leong Gene: rnf220 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1327 TCF7L2 Ivone Leong Tag Q4_21_rating tag was added to gene: TCF7L2.
Intellectual disability v3.1327 TCF7L2 Ivone Leong edited their review of gene: TCF7L2: Added comment: This gene is now associated with a relevant phenotype in Gene2Phenotype (confirmed). There is now enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; Changed rating: GREEN
Intellectual disability v3.1327 TCF7L2 Ivone Leong Phenotypes for gene: TCF7L2 were changed from Developmental disorders to Developmental disorders; Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Myopia; Abnormality of skeletal system
Intellectual disability v3.1326 TCF7L2 Ivone Leong Publications for gene: TCF7L2 were set to 33057194
Intellectual disability v3.1325 PLXNA2 Ivone Leong Classified gene: PLXNA2 as Amber List (moderate evidence)
Intellectual disability v3.1325 PLXNA2 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there are currently only 2 cases there is not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Intellectual disability v3.1325 PLXNA2 Ivone Leong Gene: plxna2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1324 PLXNA2 Ivone Leong Phenotypes for gene: PLXNA2 were changed from Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology to Intellectual disability, MONDO:0001071; Abnormality of the face; Failure to thrive; Abnormal heart morphology
Intellectual disability v3.1323 PLXNA2 Ivone Leong Tag watchlist tag was added to gene: PLXNA2.
Intellectual disability v3.1323 AIFM1 Arina Puzriakova Phenotypes for gene: AIFM1 were changed from Combined oxidative phosphorylation deficiency 6, 300816Cowchock syndrome, 310490; COWCHOCK SYNDROME to Cowchock syndrome, OMIM:310490; Combined oxidative phosphorylation deficiency 6, OMIM:300816; Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, OMIM:300232
Intellectual disability v3.1322 VPS50 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic corpus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1322 VPS50 Ivone Leong Tag watchlist tag was added to gene: VPS50.
Intellectual disability v3.1322 VPS50 Ivone Leong Tag Q3_21_rating was removed from gene: VPS50.
Intellectual disability v3.1322 VPS50 Ivone Leong Tag Q3_21_rating tag was added to gene: VPS50.
Intellectual disability v3.1322 VPS50 Ivone Leong Classified gene: VPS50 as Amber List (moderate evidence)
Intellectual disability v3.1322 VPS50 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic coprus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1322 VPS50 Ivone Leong Gene: vps50 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1321 ARF3 Ivone Leong Tag watchlist tag was added to gene: ARF3.
Intellectual disability v3.1321 ARF3 Ivone Leong Classified gene: ARF3 as Amber List (moderate evidence)
Intellectual disability v3.1321 ARF3 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:34346499, individual 1 also has severe microcephaly (-3.3SD), spasticity, cerebellum atrophy and brainstem atrophy. Individual 2 does not have microcephaly, but has cerebellar hypoplasia.

Based on the available evidence, there is currently not enough evidence to support a gene-disease association, therefore this gene has been given an Amber rating.
Intellectual disability v3.1321 ARF3 Ivone Leong Gene: arf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1320 ARF3 Ivone Leong Phenotypes for gene: ARF3 were changed from Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Global developmental delay; Intellectual disability, MONDO:0001071; Seizures; Morphological abnormality of the central nervous system; microcephaly, MONDO:0001149
Intellectual disability v3.1319 RNF113A Arina Puzriakova Phenotypes for gene: RNF113A were changed from X-linked trichothiodystrophy; Trichothiodystrophy 5, nonphotosensitive, 300953; Intellectual disability to Trichothiodystrophy 5, nonphotosensitive, OMIM:300953
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova changed review comment from: Comment on list classification: Two distinct homozygous variants identified in 5 individuals from 4 families who all presented with DD/ID. Despite indication that one of these represents a founder variants, discovery of a distinct homozygous variant in a patient with an overlapping phenotype corroborates pertinence of GTF2E2. Furthermore, there are some supportive functional studies.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.; to: Comment on list classification: Two distinct homozygous variants identified in 5 individuals from 4 families who all presented with DD/ID among other features. Despite indication that one of these represents a founder variant, discovery of a distinct homozygous variant in a patient with an overlapping phenotype corroborates pertinence of GTF2E2. Furthermore, there are some supportive in vitro studies that demonstrate functional impairment.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Amber List (moderate evidence)
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: Two distinct homozygous variants identified in 5 individuals from 4 families who all presented with DD/ID. Despite indication that one of these represents a founder variants, discovery of a distinct homozygous variant in a patient with an overlapping phenotype corroborates pertinence of GTF2E2. Furthermore, there are some supportive functional studies.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1317 GTF2E2 Arina Puzriakova Tag watchlist was removed from gene: GTF2E2.
Tag Q3_21_rating tag was added to gene: GTF2E2.
Intellectual disability v3.1317 GTF2E2 Arina Puzriakova reviewed gene: GTF2E2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26996949, 28973399; Phenotypes: Trichothiodystrophy 6, nonphotosensitive, OMIM:616943; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1317 GTF2E2 Arina Puzriakova Publications for gene: GTF2E2 were set to 30914295; 26996949
Intellectual disability v3.1316 GTF2E2 Arina Puzriakova Phenotypes for gene: GTF2E2 were changed from Trichothiodystrophy 6, nonphotosensitive, 616943 to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
Intellectual disability v3.1315 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Tag Q3_21_MOI tag was added to gene: MED12.
Tag Q3_21_expert_review tag was added to gene: MED12.
Intellectual disability v3.1315 MED12 Eleanor Williams changed review comment from: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+ female cases reported now with de novo variants in MED12 and an intellectual disability phenotype) so consideration should be given to changing the mode of inheritance to monoallelic in females.; to: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+) female cases reported now with de novo variants in MED12 and an intellectual disability phenotype so consideration should be given to changing the mode of inheritance to monoallelic in females.
Intellectual disability v3.1315 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+ female cases reported now with de novo variants in MED12 and an intellectual disability phenotype) so consideration should be given to changing the mode of inheritance to monoallelic in females.
Intellectual disability v3.1315 MED12 Eleanor Williams Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1314 MED12 Eleanor Williams Publications for gene: MED12 were set to 6711603
Intellectual disability v3.1313 MED12 Eleanor Williams edited their review of gene: MED12: Changed publications to: 33244165, 34079076, 33244166
Intellectual disability v3.1313 MED12 Eleanor Williams reviewed gene: MED12: Rating: ; Mode of pathogenicity: None; Publications: ; 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 v3.1313 CDH15 Zornitza Stark reviewed gene: CDH15: Rating: RED; Mode of pathogenicity: None; Publications: 19012874, 12052883, 28422132, 26506440; Phenotypes: Mental retardation, autosomal dominant 3, MIM#612580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1313 KMT2A Arina Puzriakova Phenotypes for gene: KMT2A were changed from WSS to Wiedemann-Steiner syndrome, OMIM:605130
Intellectual disability v3.1312 EIF2AK2 Arina Puzriakova Tag missense tag was added to gene: EIF2AK2.
Intellectual disability v3.1312 EIF2AK2 Arina Puzriakova Publications for gene: EIF2AK2 were set to 32197074
Intellectual disability v3.1311 EIF2AK2 Arina Puzriakova edited their review of gene: EIF2AK2: Added comment: A further 5 families reported (PMID: 33236446) harbouring 3 different variants in this gene (including the first homozygous case). Clinical presentation was prominent in all cases for dystonia with onset in infancy or childhood, with subsequent generalisation. 3 unrelated individuals additionally developed mild ID, spasticity, and brain MRI alterations; while 6 individuals from the remaining 2 families had only isolated dystonia.; Changed publications to: 32197074, 33236446
Intellectual disability v3.1311 EIF2AK2 Arina Puzriakova Phenotypes for gene: EIF2AK2 were changed from Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness to Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, OMIM:618877
Intellectual disability v3.1310 CPE Arina Puzriakova Publications for gene: CPE were set to 26120850; 32936766
Intellectual disability v3.1309 CPE Arina Puzriakova Classified gene: CPE as Amber List (moderate evidence)
Intellectual disability v3.1309 CPE Arina Puzriakova Added comment: Comment on list classification: There are now sufficient unrelated families (5) reported in literature presenting a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1309 CPE Arina Puzriakova Gene: cpe has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1308 CPE Arina Puzriakova Tag watchlist was removed from gene: CPE.
Tag Q3_21_rating tag was added to gene: CPE.
Intellectual disability v3.1308 CPE Arina Puzriakova edited their review of gene: CPE: Added comment: Bosch et al. 2021 (PMID: 34383079) reported on 4 individuals from 3 additional families harbouring 2 different homozygous truncating variants in this gene. Clinical presentation was prominent for obesity and intellectual disability. Hypogonadotropic hypogonadism was confirmed in one individual and was suspected but not tested for in another two subjects.; Changed rating: GREEN; Changed publications to: 26120850, 32936766, 34383079; Changed phenotypes to: Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1308 PCDHGC4 Sarah Leigh Classified gene: PCDHGC4 as Amber List (moderate evidence)
Intellectual disability v3.1308 PCDHGC4 Sarah Leigh Added comment: Comment on list classification: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1308 PCDHGC4 Sarah Leigh Gene: pcdhgc4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1307 PCDHGC4 Sarah Leigh Deleted their comment
Intellectual disability v3.1307 PCDHGC4 Sarah Leigh Phenotypes for gene: PCDHGC4 were changed from neurodevelopmental syndrome to Neurodevelopmental abnormality HP:0012759
Intellectual disability v3.1306 KIRREL3 Aleš Maver reviewed gene: KIRREL3: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 33853164; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1306 PITRM1 Ivone Leong Phenotypes for gene: PITRM1 were changed from Ataxia; Intellectual disability to Spinocerebellar ataxia, autosomal recessive 30, OMIM:619405
Intellectual disability v3.1305 ATP1A3 Zornitza Stark Deleted their comment
Intellectual disability v3.1305 TNPO2 Arina Puzriakova Classified gene: TNPO2 as Amber List (moderate evidence)
Intellectual disability v3.1305 TNPO2 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there are now sufficient unrelated cases with a relevant phenotype associated with various variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1305 TNPO2 Arina Puzriakova Gene: tnpo2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1304 TNPO2 Arina Puzriakova Mode of inheritance for gene: TNPO2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1303 TNPO2 Arina Puzriakova Phenotypes for gene: TNPO2 were changed from to Intellectual disability; Dysmorphic features; Microcephaly; Seizures; Hypotonia
Intellectual disability v3.1302 TNPO2 Arina Puzriakova Publications for gene: TNPO2 were set to 26350204
Intellectual disability v3.1301 TNPO2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: TNPO2.
Intellectual disability v3.1301 TNPO2 Arina Puzriakova reviewed gene: TNPO2: Rating: ; Mode of pathogenicity: None; Publications: 34314705; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1301 LINGO4 Arina Puzriakova Classified gene: LINGO4 as Amber List (moderate evidence)
Intellectual disability v3.1301 LINGO4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There a sufficient unrelated cases with a relevant phenotype to rate as Green at the next GMS panel update.
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PMID: 33098801 - 4 individuals from 3 unrelated families harbouring private biallelic variants in this gene which co-segregated with disease. 4/4 cases presented with GDD and ID.
Intellectual disability v3.1301 LINGO4 Arina Puzriakova Gene: lingo4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1300 LINGO4 Arina Puzriakova Tag Q3_21_rating tag was added to gene: LINGO4.
Intellectual disability v3.1300 IMPDH2 Arina Puzriakova Classified gene: IMPDH2 as Amber List (moderate evidence)
Intellectual disability v3.1300 IMPDH2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not yet associated with a relevant phenotype in OMIM or G2P, but sufficient unrelated cases with relevant phenotype to rate Green at the next GMS review. Neurodevelopmental delay is an early feature that may be evident prior to other manifestations (plausible that other cases may develop dystonic signs later in life) and so inclusion on this panel is warranted.
Intellectual disability v3.1300 IMPDH2 Arina Puzriakova Gene: impdh2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1299 IMPDH2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: IMPDH2.
Intellectual disability v3.1299 IMPDH2 Arina Puzriakova reviewed gene: IMPDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33098801; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Tag Q3_21_rating tag was added to gene: CLCN3.
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Classified gene: CLCN3 as Amber List (moderate evidence)
Intellectual disability v3.1299 CLCN3 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. Sufficient number of unrelated cases with relevant phenotype to add to the ID and epilepsy panels. Functional studies and animal model support pathogenicity. CLCN3 is also associated with a relevant phenotype in OMIM (MIM# 619512 and 619517)
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Gene: clcn3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1298 CLCN3 Arina Puzriakova Mode of inheritance for gene: CLCN3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.1297 CLCN3 Arina Puzriakova Phenotypes for gene: CLCN3 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517
Intellectual disability v3.1296 ANK2 Arina Puzriakova Classified gene: ANK2 as Amber List (moderate evidence)
Intellectual disability v3.1296 ANK2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel review - sufficient unrelated cases with relevant phenotype and de novo PTVs in this gene. Definitive gene-disease association is supported by the ClinGen ID and Autism Expert Panel.
Intellectual disability v3.1296 ANK2 Arina Puzriakova Gene: ank2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1295 ANK2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: ANK2.
Intellectual disability v3.1295 TP73 Arina Puzriakova Publications for gene: TP73 were set to 31130284
Intellectual disability v3.1295 TP73 Arina Puzriakova Classified gene: TP73 as Amber List (moderate evidence)
Intellectual disability v3.1295 TP73 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel review - at least 7 unrelated families with distinct variants and relevant phenotypes. Supported by some functional data.

TP73 is also now associated with a relevant phenotype in OMIM (MIM# 619466) but is not yet listed in G2P.
Intellectual disability v3.1295 TP73 Arina Puzriakova Gene: tp73 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1294 TP73 Arina Puzriakova Tag Q3_21_rating tag was added to gene: TP73.
Intellectual disability v3.1294 TP73 Arina Puzriakova edited their review of gene: TP73: Changed rating: GREEN; Changed publications to: 31130284, 34077761; Changed phenotypes to: Ciliary dyskinesia, primary, 47, and lissencephaly, OMIM:619466
Intellectual disability v3.1294 TP73 Arina Puzriakova commented on gene: TP73: PMID: 34077761 (2021) - Further 7 individuals from 5 families identified with different homozygous variants in this gene. All affected individuals exhibited cortical malformations characterised by lissencephaly, central muscular hypotonia and moderate to severe cognitive dysfunction.
Intellectual disability v3.1294 TP73 Arina Puzriakova Phenotypes for gene: TP73 were changed from Intellectual disability; lissencephaly to Ciliary dyskinesia, primary, 47, and lissencephaly, OMIM:619466
Intellectual disability v3.1293 AP1G1 Arina Puzriakova Mode of inheritance for gene AP1G1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1292 AP1G1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: AP1G1.
Intellectual disability v3.1292 AP1G1 Arina Puzriakova Classified gene: AP1G1 as Amber List (moderate evidence)
Intellectual disability v3.1292 AP1G1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Usmani et al., 2021 (PMID: 34102099) identified 9 families with heterozygous and 2 families with homozygous variants in this gene. All individuals (12) had GDD and ID of various severity (mild to severe), except one patient who died at 22 days. Other features include hypotonia (9/10), seizures (6/10) and spasticity (4/10). Some supportive functional data included.

There is sufficient evidence to promote this gene to Green at the next GMS panel update, with 'monoallelic' MOI. Biallelic cases would still be picked up by the Genomics England pipeline - but this may be reviewed if additional cases are discovered.
Intellectual disability v3.1292 AP1G1 Arina Puzriakova Gene: ap1g1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1291 ATP9A Arina Puzriakova Publications for gene: ATP9A were set to
Intellectual disability v3.1290 ATP9A Arina Puzriakova Classified gene: ATP9A as Amber List (moderate evidence)
Intellectual disability v3.1290 ATP9A Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases/clinical evidence.
Intellectual disability v3.1290 ATP9A Arina Puzriakova Gene: atp9a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1289 CAMK4 Arina Puzriakova Classified gene: CAMK4 as Amber List (moderate evidence)
Intellectual disability v3.1289 CAMK4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There are sufficient unrelated cases (3) presenting with a relevant phenotype in association with different variants in the CAMK4 gene.
Intellectual disability v3.1289 CAMK4 Arina Puzriakova Gene: camk4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1288 CAMK4 Arina Puzriakova Tag Q3_21_rating tag was added to gene: CAMK4.
Intellectual disability v3.1288 CAMK4 Arina Puzriakova Mode of pathogenicity for gene: CAMK4 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 v3.1287 SYNCRIP Arina Puzriakova Phenotypes for gene: SYNCRIP were changed from to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Intellectual disability v3.1286 SYNCRIP Arina Puzriakova Publications for gene: SYNCRIP were set to 27479843; 26350204
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Tag watchlist was removed from gene: SYNCRIP.
Tag Q3_21_rating tag was added to gene: SYNCRIP.
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Classified gene: SYNCRIP as Amber List (moderate evidence)
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there are sufficient unrelated cases to rate as Green at the next GMS review. All individuals reported to date have presented with ID of various severity as the predominant feature.
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Gene: syncrip has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1284 SYNCRIP Arina Puzriakova Mode of inheritance for gene: SYNCRIP was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1283 HIST1H4C Ivone Leong Tag watchlist was removed from gene: HIST1H4C.
Tag Q3_21_rating tag was added to gene: HIST1H4C.
Intellectual disability v3.1283 HIST1H4C Ivone Leong reviewed gene: HIST1H4C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1283 ATP1A3 Arina Puzriakova Publications for gene: ATP1A3 were set to 22842232; 29396171; 29291920; 22842232; 28969699; 32802951
Intellectual disability v3.1282 ATP1A3 Arina Puzriakova Tag Q3_21_expert_review tag was added to gene: ATP1A3.
Intellectual disability v3.1282 ATP1A3 Arina Puzriakova commented on gene: ATP1A3: Gene was reassessed following a further Green review by Zornitza Stark (8 Jul 2021). Vetro et al. (PMID: 33880529) identified several individuals with variants in this gene who presented with DD/ID as the predominant feature. Therefore, ATP1A3 will be flagged for GMS expert review as inclusion on this panel may be of value in some patients but previous comments regarding association with several phenotypes should be considered.
Intellectual disability v3.1282 CPE Dmitrijs Rots reviewed gene: CPE: Rating: GREEN; Mode of pathogenicity: None; Publications: 34383079; Phenotypes: Obesity, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1282 RFX3 Arina Puzriakova Phenotypes for gene: RFX3 were changed from ID, ASD, ADHD to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258; Attention deficit-hyperactivity disorder, MONDO:0007743
Intellectual disability v3.1282 RFX7 Arina Puzriakova Phenotypes for gene: RFX7 were changed from Intellectual disability, MONDO:0001071, autism spectrum disorder, MONDO:0005258, attention deficit-hyperactivity disorder, MONDO:0007743 to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258; Attention deficit-hyperactivity disorder, MONDO:0007743
Intellectual disability v3.1281 RFX4 Arina Puzriakova Phenotypes for gene: RFX4 were changed from ID, ASD, ADHD to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258
Intellectual disability v3.1280 RFX7 Arina Puzriakova Classified gene: RFX7 as Amber List (moderate evidence)
Intellectual disability v3.1280 RFX7 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 14 unrelated individuals were identified with different variants in the RFX7 gene (13 de novo, 1 unknown). Presenting phenotypes were predominantly of ID/GDD (13/14) and dysmorphism (12/14).

There are sufficient unrelated cases with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1280 RFX7 Arina Puzriakova Gene: rfx7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1279 RFX4 Arina Puzriakova Classified gene: RFX4 as Amber List (moderate evidence)
Intellectual disability v3.1279 RFX4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 6 individuals from 4 unrelated families were identified with different variants in the RFX4 gene (3 de novo, 1 inherited). Presenting phenotypes include ID/GDD (6/6) and ASD (5/6).

There are sufficient unrelated cases with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1279 RFX4 Arina Puzriakova Gene: rfx4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1278 RFX7 Arina Puzriakova Tag Q3_21_rating tag was added to gene: RFX7.
Intellectual disability v3.1278 RFX4 Arina Puzriakova Tag Q3_21_rating tag was added to gene: RFX4.
Intellectual disability v3.1278 RFX3 Arina Puzriakova Tag Q3_21_rating tag was added to gene: RFX3.
Intellectual disability v3.1278 RFX3 Arina Puzriakova Classified gene: RFX3 as Amber List (moderate evidence)
Intellectual disability v3.1278 RFX3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 18 individuals from 15 unrelated families were identified with different heterozygous variants in the RFX3 gene (14 de novo, 1 inherited). Presenting phenotypes include ID/GDD (14/18), ASD (13/18) and ADHD (10/18).

There are sufficient unrelated cases with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1278 RFX3 Arina Puzriakova Gene: rfx3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1277 EIF2AK2 Dmitrijs Rots reviewed gene: EIF2AK2: 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: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1277 COPB2 Eleanor Williams Classified gene: COPB2 as Amber List (moderate evidence)
Intellectual disability v3.1277 COPB2 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber with a recommendation for green rating following GMS review.
Intellectual disability v3.1277 COPB2 Eleanor Williams Gene: copb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1276 COPB2 Eleanor Williams Tag Q3_21_rating tag was added to gene: COPB2.
Intellectual disability v3.1276 COPB2 Eleanor Williams changed review comment from: PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals with variable severity. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass
Sources: Literature; to: PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals with variable severity. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass

PMID: 29036432 - original report of microcephaly in the two siblings with the COPB2 homozygous variant.
Intellectual disability v3.1276 COPB2 Eleanor Williams Added comment: Comment on mode of inheritance: 4 families with heterozygous variants and 1 with biallelic (more severe phenotype)
Intellectual disability v3.1276 COPB2 Eleanor Williams Mode of inheritance for gene: COPB2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1275 COPB2 Eleanor Williams gene: COPB2 was added
gene: COPB2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: COPB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COPB2 were set to 34450031
Phenotypes for gene: COPB2 were set to osteoporosis; developmental delay
Review for gene: COPB2 was set to GREEN
Added comment: PMID: 34450031 - Marom et al 2021 describes 6 individuals from 5 families. In 4 families loss of function heterozygous variants in COPB2 were found. In the 5th family, two affected siblings were found to have a homozygous variant in COPB2. Osteopenia was noted in 4/5 families (5th unknown) and fractures in 2/5. Developmental delay was observed in all 6 individuals with variable severity. Severe intellectual disability, seizures and microcephaly was noted in the siblings with the homozygous variants. Copb2þ +/-mice exhibit low bone mass
Sources: Literature
Intellectual disability v3.1274 HID1 Arina Puzriakova Tag Q3_21_rating tag was added to HID1.
Intellectual disability v3.1273 HID1 Arina Puzriakova Classified gene: HID1 as Amber List (moderate evidence)
Intellectual disability v3.1273 HID1 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.
Intellectual disability v3.1273 HID1 Arina Puzriakova Gene: hid1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1272 HID1 Arina Puzriakova reviewed gene: HID1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33999436; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1272 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Intellectual disability v3.1272 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from to None
Intellectual disability v3.1271 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, 617820; NDHMSR; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, 614254; NDHMSD; Mental retardation, autosomal dominant 8, 614254; EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Intellectual disability v3.1270 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome to Kabuki syndrome 1, OMIM:147920
Intellectual disability v3.1269 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Intellectual disability v3.1269 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, OMIM:616973 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Intellectual disability v3.1268 MYO1H Sarah Leigh Entity copied from Familial dysautonomia v1.15
Intellectual disability v3.1268 MYO1H Sarah Leigh gene: MYO1H was added
gene: MYO1H was added to Intellectual disability. Sources: Expert Review Red,Literature
Mode of inheritance for gene: MYO1H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO1H were set to 28779001
Phenotypes for gene: MYO1H were set to ?Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction OMIM:619482
Intellectual disability v3.1267 PGRMC1 Ivone Leong Publications for gene: PGRMC1 were set to
Intellectual disability v3.1266 PGRMC1 Ivone Leong reviewed gene: PGRMC1: Rating: ; Mode of pathogenicity: None; Publications: 33867527; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1266 TRAPPC10 Ivone Leong Phenotypes for gene: TRAPPC10 were changed from microcephaly (disease), MONDO:0001149 to Intellectual disability, MONDO:0001071
Intellectual disability v3.1265 TRAPPC10 Ivone Leong Entity copied from Severe microcephaly v2.223
Intellectual disability v3.1265 TRAPPC10 Ivone Leong gene: TRAPPC10 was added
gene: TRAPPC10 was added to Intellectual disability. Sources: Expert Review Red,Other
Mode of inheritance for gene: TRAPPC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC10 were set to 30167849
Phenotypes for gene: TRAPPC10 were set to microcephaly (disease), MONDO:0001149
Penetrance for gene: TRAPPC10 were set to Complete
Intellectual disability v3.1264 ATP1A2 Arina Puzriakova Publications for gene: ATP1A2 were set to 15159495; 29610157
Intellectual disability v3.1263 PARP6 Arina Puzriakova Classified gene: PARP6 as Amber List (moderate evidence)
Intellectual disability v3.1263 PARP6 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. At least 3 individuals with heterozygous PARP6 variants and a relevant phenotype have been reported (PMID: 34067418) - however, segregation analysis has only been complete for one of these cases. Furthermore, identification of two sibs with biallelic variants and unaffected parents who were heterozygous carriers arises possibility of incomplete penetrance or role of variants in other genes.

Overall there is not enough evidence to add this gene as diagnostic grade, so rating Amber with watchlist tag.
Intellectual disability v3.1263 PARP6 Arina Puzriakova Gene: parp6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1262 PARP6 Arina Puzriakova Tag watchlist tag was added to gene: PARP6.
Intellectual disability v3.1262 PARP6 Arina Puzriakova reviewed gene: PARP6: Rating: ; Mode of pathogenicity: None; Publications: 34067418; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1262 ZNF668 Zornitza Stark gene: ZNF668 was added
gene: ZNF668 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF668 were set to 34313816; 26633546
Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism
Review for gene: ZNF668 was set to AMBER
Added comment: 2 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature
Intellectual disability v3.1262 PRICKLE2 Zornitza Stark reviewed gene: PRICKLE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34092786; Phenotypes: Neurodevelopmental disorder, global developmental delay, behavioural difficulties ± epilepsy, autistic features, attention deficit hyperactive disorder, psychiatric symptoms; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1262 UBE2U Zornitza Stark gene: UBE2U was added
gene: UBE2U was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBE2U were set to 33776059
Phenotypes for gene: UBE2U were set to Retinoschisis; cataracts; learning disabilities; developmental delay
Review for gene: UBE2U was set to RED
Added comment: Single family with 5 individuals reported.
Sources: Literature
Intellectual disability v3.1262 CACNA1I Zornitza Stark gene: CACNA1I was added
gene: CACNA1I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1I were set to 33704440
Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CACNA1I was set to Other
Review for gene: CACNA1I was set to GREEN
gene: CACNA1I was marked as current diagnostic
Added comment: 4 different missense variants identified and shown to result in a gain of function.

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

1 family had three affected individuals - variable cognitive impairment in all, involving borderline intellectual functioning or mild or moderate intellectual disability as main clinical feature, with late-onset seizures in the mother and speech retardation in one of the children. This variant had a milder functional effect than the variants in sporadic cases.
Sources: Literature
Intellectual disability v3.1262 GRIK2 Zornitza Stark reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34375587, 17847003, 25039795; Phenotypes: Mental retardation, autosomal recessive, 6 MIM# 611092, Non-syndromic neurodevelopmental disorder (NDD), autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1262 CHRM1 Zornitza Stark gene: CHRM1 was added
gene: CHRM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHRM1 were set to 34212451; 31981491; 12483218
Phenotypes for gene: CHRM1 were set to Neurodevelopmental delay; intellectual disability; autism
Review for gene: CHRM1 was set to AMBER
Added comment: PMID: 34212451 - 2 unrelated cases with de novo missense variants (p.Pro380Leu and p.Phe425Ser), one case with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and the second case with mild dysmorphism, global developmental delay, and moderate intellectual disability. In vitro biochemical analyses of p.Pro380Leu demonstrated a reduction in protein levels, impaired cellular trafficking, and defective activation of intracellular signaling pathways.
PMID: 31981491 - an autism spectrum disorder (no other information on phenotype, except ascertained to have severe neurodevelopmental delay) case with a de novo missense variant p.(Arg210Leu)
PMID: 12483218 - null mouse model assessing memory demonstrated selective cognitive dysfunction.
Sources: Literature
Intellectual disability v3.1262 ZNF699 Zornitza Stark gene: ZNF699 was added
gene: ZNF699 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF699 were set to 33875846
Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome, MIM# 619488
Review for gene: ZNF699 was set to GREEN
Added comment: DEGCAGS syndrome is a neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anaemia or pancytopaenia, and immunodeficiency with recurrent infections.

12 unrelated families reported, 5 different homozygous frameshift variants.
Sources: Literature
Intellectual disability v3.1262 TCF7L2 Zornitza Stark edited their review of gene: TCF7L2: Added comment: Additional 11 cases reported.; Changed rating: GREEN; Changed publications to: 33057194, 34003604
Intellectual disability v3.1262 JAKMIP1 Zornitza Stark gene: JAKMIP1 was added
gene: JAKMIP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model. Patient 1 (27799067) with developmental delay, speech delay, and cognitive impairment; self-injurious and aggressive behaviour, seizures, dysmorphic features. De-novo missense JAKMIP1 (p.D586H). Patient 2 (29158550) with feeding difficulties, hypotonia, epilepsy, severe ID, no active speech, kyphoscoliosis, constipation, autism, short stature. Splice variant c.1432-2A>G, no segregation or RNA data available. KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors.
Sources: Literature
Intellectual disability v3.1262 EML1 Arina Puzriakova Phenotypes for gene: EML1 were changed from congenital hydrocephalus, profound global developmental delay and intractable epilepsy; Band heterotopia, 600348 (includes severe intellectual disability) to Band heterotopia, OMIM:600348
Intellectual disability v3.1261 DEPDC5 Arina Puzriakova Phenotypes for gene: DEPDC5 were changed from FAMILIAL FOCAL EPILEPSY WITH VARIABLE FOCI (FFEVF) to Epilepsy, familial focal, with variable foci 1, OMIM:604364
Intellectual disability v3.1260 DCHS1 Arina Puzriakova Phenotypes for gene: DCHS1 were changed from PERIVENTRICULAR NEURONAL HETEROTOPIA; Van Maldergem syndrome 1, 601390 to Van Maldergem syndrome 1, OMIM:601390
Intellectual disability v3.1259 CTNNA2 Arina Puzriakova Phenotypes for gene: CTNNA2 were changed from Cortical dysplasia, complex, with other brain malformations 9, 618174; intellectual disability; global developmental delay to Cortical dysplasia, complex, with other brain malformations 9, OMIM:618174
Intellectual disability v3.1258 CSNK2A1 Arina Puzriakova Phenotypes for gene: CSNK2A1 were changed from Okur-Chung neurodevelopmental syndrome to Okur-Chung neurodevelopmental syndrome, OMIM:617062
Intellectual disability v3.1257 PIDD1 Arina Puzriakova Classified gene: PIDD1 as Amber List (moderate evidence)
Intellectual disability v3.1257 PIDD1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Overall there are sufficient unrelated cases (>3) with a relevant phenotype and biallelic variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1257 PIDD1 Arina Puzriakova Gene: pidd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1256 PIDD1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: PIDD1.
Intellectual disability v3.1256 CRADD Arina Puzriakova Phenotypes for gene: CRADD were changed from Mental retardation, autosomal recessive 34, with variant lissencephaly 614499 to Mental retardation, autosomal recessive 34, with variant lissencephaly, OMIM:614499
Intellectual disability v3.1255 CRADD Arina Puzriakova Publications for gene: CRADD were set to 22279524; 27773430
Intellectual disability v3.1254 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome, 118450; Tetralogy of Fallot, 187500; Deafness, congenital heart defects, and posterior embryotoxon to Alagille syndrome 1, OMIM:118450
Intellectual disability v3.1253 JAG1 Arina Puzriakova Mode of inheritance for gene: JAG1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1252 ARF1 Arina Puzriakova edited their review of gene: ARF1: Added comment: Added to ID panel as developmental delay (especially in speech) is a reported feature in all cases (except for one individuals for which only limited clinical information was available). Although only one patient has been reported with a moderate ID diagnosis, developmental delay is likely to be noticed earlier in the course of disease than cortical malformations and may prompt genetic investigation. Inclusion on this panel could increase the likelihood of detecting cases and therefore a Green rating is warranted.; Changed rating: GREEN; Changed publications to: 28868155, 34353862; Changed phenotypes to: Periventricular nodular heterotopia 8, OMIM:618185; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1252 ARF1 Arina Puzriakova Entity copied from Malformations of cortical development v2.62
Intellectual disability v3.1252 ARF1 Arina Puzriakova gene: ARF1 was added
gene: ARF1 was added to Intellectual disability. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: ARF1.
Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF1 were set to 28868155; 34353862
Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8, OMIM:618185
Intellectual disability v3.1251 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 615351; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 OMIM:615350; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 MONDO:0014140; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 OMIM:615351; muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 MONDO:0014141; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Intellectual disability v3.1250 KMT2E Arina Puzriakova Added comment: Comment on publications: PMID: 34321323 - 18 additional patients from 17 families with genetically confirmed ODLURO
Intellectual disability v3.1250 KMT2E Arina Puzriakova Publications for gene: KMT2E were set to 31079897
Intellectual disability v3.1249 MAP1B Arina Puzriakova Tag Q3_21_rating tag was added to gene: MAP1B.
Intellectual disability v3.1249 MAP1B Arina Puzriakova edited their review of gene: MAP1B: Added comment: MAP1B was flagged by a GLH following identification of some potential cases relating to variants in this gene and predominantly ID phenotypes within 100K data. Although these are pending confirmations (will request update once cases are validated), upon reassessment of MAP1B it was highlighted that inclusion on this panels may still be warranted to increase the likelihood of detecting cases, particularly given that DD/ID is more likely to be observed earlier in the course of disease albeit at varying severities.

For this reason, MAP1B should be promoted to Green status at the next GMS panel review (tagged Q3_21_rating); Changed rating: GREEN
Intellectual disability v3.1249 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.233
Intellectual disability v3.1249 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Intellectual disability. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Intellectual disability v3.1248 ASXL3 Arina Puzriakova Publications for gene: ASXL3 were set to 23383720
Intellectual disability v3.1247 ASXL3 Arina Puzriakova Phenotypes for gene: ASXL3 were changed from BAINBRIDGE-ROPERS SYNDROME; BRPS to Bainbridge-Ropers syndrome, OMIM:615485
Intellectual disability v3.1246 SLC25A15 Arina Puzriakova Phenotypes for gene: SLC25A15 were changed from Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, 238970 -3; HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME (HHH SYNDROME) to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970
Intellectual disability v3.1245 GALC Arina Puzriakova Phenotypes for gene: GALC were changed from KRABBE DISEASE to Krabbe disease, OMIM:245200
Intellectual disability v3.1244 ALDH3A2 Arina Puzriakova Phenotypes for gene: ALDH3A2 were changed from Sjogren-Larsson syndrome, 270200; SJOEGREN-LARSSON SYNDROME (SLS) to Sjogren-Larsson syndrome, OMIM:270200
Intellectual disability v3.1243 SLC16A2 Arina Puzriakova Phenotypes for gene: SLC16A2 were changed from Allan-Herndon-Dudley syndrome, 300523; MCT8 (SLC16A2)-SPECIFIC THYROID HORMONE CELL TRANSPORTER DEFICIENCY to Allan-Herndon-Dudley syndrome, OMIM:300523
Intellectual disability v3.1242 L1CAM Arina Puzriakova Phenotypes for gene: L1CAM were changed from Hydrocephalus due to aqueductal stenosis, 307000MASA syndrome, 303350CRASH syndrome, 303350Hydrocephalus with Hirschsprung disease, 307000Hydrocephalus with congenital idiopathic intestinal pseudoobstruction, 307000Corpus callosum, partial agenesis of, 304100; MENTAL RETARDATION-APHASIA-SHUFFLING GAIT-ADDUCTED THUMBS SYNDROME (MASA) to Corpus callosum, partial agenesis of, OMIM:304100; CRASH syndrome, OMIM:303350; MASA syndrome, OMIM:303350; Hydrocephalus due to aqueductal stenosis, OMIM:307000; Hydrocephalus with congential idiopathic intestinal pseudoobstruction, OMIM:307000; Hydrocephalus with Hirschsprung disease, OMIM:307000
Intellectual disability v3.1241 C12orf65 Arina Puzriakova Phenotypes for gene: C12orf65 were changed from COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 7 to Combined oxidative phosphorylation deficiency 7, OMIM:613559; Spastic paraplegia 55, autosomal recessive, OMIM:615035
Intellectual disability v3.1240 WDR45B Arina Puzriakova Phenotypes for gene: WDR45B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977 to Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, OMIM:617977
Intellectual disability v3.1239 TFG Arina Puzriakova Phenotypes for gene: TFG were changed from Hereditary motor and sensory neuropathy, proximal type, 604484; ?Spastic paraplegia 57, autosomal recessive, 615658 to Spastic paraplegia 57, autosomal recessive, OMIM:615658
Intellectual disability v3.1238 WDR11 Konstantinos Varvagiannis reviewed gene: WDR11: Rating: AMBER; Mode of pathogenicity: None; Publications: 34413497; Phenotypes: Intellectual disability, Microcephaly, Short stature; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1238 SPART Arina Puzriakova Phenotypes for gene: SPART were changed from Troyer syndrome; MIM:275900; developmental delay to Troyer syndrome, OMIM:275900
Intellectual disability v3.1237 SERAC1 Arina Puzriakova Phenotypes for gene: SERAC1 were changed from 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 614739; MEGDEL syndrome; 3-MEthylGlutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome; MEGDHEL syndrome; Intellectual disability to 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, OMIM:614739
Intellectual disability v3.1236 KDM5C Arina Puzriakova Tag Q3_21_MOI tag was added to gene: KDM5C.
Intellectual disability v3.1236 KIF1C Arina Puzriakova Phenotypes for gene: KIF1C were changed from Spastic ataxia 2, autosomal recessive, 611302 to Spastic ataxia 2, autosomal recessive, OMIM:611302
Intellectual disability v3.1235 KIDINS220 Arina Puzriakova Publications for gene: KIDINS220 were set to 27005418
Intellectual disability v3.1234 KDM5C Arina Puzriakova Publications for gene: KDM5C were set to
Intellectual disability v3.1233 KDM5C Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'X-linked.. biallelic in females' to 'X-linked.. monoallelic in females may cause disease' at the next GMS panel update.

A subset of female carriers have been shown to have impaired intellectual development and/or developmental delay (PMIDs: 10982473; 16538222; 18697827; 19826449; 21575681; 32279304)

This also reflects the current MOI on all other relevant panels.
Intellectual disability v3.1233 KDM5C Arina Puzriakova Mode of inheritance for gene: KDM5C was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1232 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534 -3; MENTAL RETARDATION SYNDROMIC X-LINKED JARID1C-RELATED (MRXSJ) to Mental retardation, X-linked, syndromic, Claes-Jensen type, OMIM:300534
Intellectual disability v3.1231 HACE1 Arina Puzriakova Publications for gene: HACE1 were set to
Intellectual disability v3.1230 FIG4 Sarah Leigh Tag Q3_21_MOI was removed from gene: FIG4.
Intellectual disability v3.1230 FIG4 Sarah Leigh Phenotypes for gene: FIG4 were changed from CHARCOT-MARIE-TOOTH DISEASE, TYPE 4J to Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Charcot-Marie-Tooth disease type 4J MONDO:0012640; Yunis Varon syndrome OMIM:216340; Yunis-Varon syndrome MONDO:0008995
Intellectual disability v3.1229 FIG4 Sarah Leigh Publications for gene: FIG4 were set to 17572665
Intellectual disability v3.1228 FIG4 Sarah Leigh Tag Q3_21_MOI tag was added to gene: FIG4.
Intellectual disability v3.1228 HNMT Ivone Leong Phenotypes for gene: HNMT were changed from Mental retardation, autosomal recessive 51, MIM#616739 to Mental retardation, autosomal recessive 51, OMIM:616739
Intellectual disability v3.1227 HNMT Ivone Leong reviewed gene: HNMT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1227 HNMT Ivone Leong Tag watchlist was removed from gene: HNMT.
Tag Q3_21_rating tag was added to gene: HNMT.
Tag Q3_21_NHS_review tag was added to gene: HNMT.
Intellectual disability v3.1227 HNMT Ivone Leong Publications for gene: HNMT were set to 26206890; 30744146
Intellectual disability v3.1226 ENTPD1 Arina Puzriakova Classified gene: ENTPD1 as Amber List (moderate evidence)
Intellectual disability v3.1226 ENTPD1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as there is some evidence of cognitive impairment associated with SPG64, but perhaps too mild in most cases to warrant inclusion on this panel. Cases are expected to be picked up via the HSP route which presents a more prominent feature of this disorder.
Intellectual disability v3.1226 ENTPD1 Arina Puzriakova Gene: entpd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1225 ENTPD1 Arina Puzriakova Publications for gene: ENTPD1 were set to 21937992
Intellectual disability v3.1224 ENTPD1 Arina Puzriakova Phenotypes for gene: ENTPD1 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Spastic paraplegia 64, autosomal recessive, OMIM:615683
Intellectual disability v3.1223 ENTPD1 Arina Puzriakova reviewed gene: ENTPD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24482476, 29691679, 30652007; Phenotypes: Spastic paraplegia 64, autosomal recessive, OMIM:615683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1223 ARG1 Arina Puzriakova Phenotypes for gene: ARG1 were changed from Argininemia, 207800; ARGININEMIA (ARGIN) to Argininemia, OMIM:207800
Intellectual disability v3.1222 RNF220 Konstantinos Varvagiannis gene: RNF220 was added
gene: RNF220 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Penetrance for gene: RNF220 were set to Complete
Review for gene: RNF220 was set to GREEN
Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal.

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

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

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

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

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

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

Consider inclusion in panels for leukodystrophies, childhood onset ataxia, sensorineural hearing loss, corpus callosum anomalies, cardiomyopathies, hepatopathies, etc in all cases with green rating.
Sources: Literature, Other
Intellectual disability v3.1222 ALS2 Arina Puzriakova Phenotypes for gene: ALS2 were changed from ALS2-RELATED DISORDERS; Amyotrophic lateral sclerosis 2, juvenile, 205100 to Amyotrophic lateral sclerosis 2, juvenile, OMIM:205100; Primary lateral sclerosis, juvenile, OMIM:606353; Spastic paralysis, infantile onset ascending, OMIM:607225
Intellectual disability v3.1221 AIMP1 Arina Puzriakova Phenotypes for gene: AIMP1 were changed from Leukodystrophy, hypomyelinating, 3, 260600; LEUKODYSTROPHY, HYPOMYELINATING, 3 to Leukodystrophy, hypomyelinating, 3, OMIM:260600
Intellectual disability v3.1220 ARF3 Konstantinos Varvagiannis gene: ARF3 was added
gene: ARF3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARF3 were set to 34346499
Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: ARF3 were set to unknown
Review for gene: ARF3 was set to AMBER
Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality.

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

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

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

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

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

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

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

Evidence to support the effect of each variant include:

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

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

There is no associated phenotype in OMIM, G2P or SysID.
Sources: Literature
Intellectual disability v3.1220 PLXNA2 Konstantinos Varvagiannis changed review comment from: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

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

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

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

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

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

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

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

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

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature, Other; to: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

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

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

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

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

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

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

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

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

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature, Other
Intellectual disability v3.1220 PLXNA2 Konstantinos Varvagiannis gene: PLXNA2 was added
gene: PLXNA2 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: PLXNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNA2 were set to 34327814
Phenotypes for gene: PLXNA2 were set to Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology
Penetrance for gene: PLXNA2 were set to Incomplete
Review for gene: PLXNA2 was set to AMBER
Added comment: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants.

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

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

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

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

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

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

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

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

There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes.
Sources: Literature, Other
Intellectual disability v3.1220 VPS50 Konstantinos Varvagiannis gene: VPS50 was added
gene: VPS50 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

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

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

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

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

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

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

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

Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports.
Sources: Literature
Intellectual disability v3.1220 HNMT Sarah Graham reviewed gene: HNMT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26206890, 33310825, 33739554; Phenotypes: Intellectual disability, 616739; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1220 CTC1 Arina Puzriakova Phenotypes for gene: CTC1 were changed from CEREBRORETINAL MICROANGIOPATHY WITH CALCIFICATIONS AND CYSTS to Cerebroretinal microangiopathy with calcifications and cysts, OMIM:612199
Intellectual disability v3.1219 CTC1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: CTC1.
Intellectual disability v3.1219 CTC1 Arina Puzriakova Classified gene: CTC1 as Green List (high evidence)
Intellectual disability v3.1219 CTC1 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Amber, as per the recent review by Zornitza Stark. The disorder is primarily characterised by intracranial calcifications to which cognitive decline is secondary. Some individuals have normal cognition.
Intellectual disability v3.1219 CTC1 Arina Puzriakova Gene: ctc1 has been classified as Green List (High Evidence).
Intellectual disability v3.1218 PGM2L1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: PGM2L1.
Intellectual disability v3.1218 PGM2L1 Arina Puzriakova Classified gene: PGM2L1 as Amber List (moderate evidence)
Intellectual disability v3.1218 PGM2L1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update (tagged).

Morava et al. 2021 (PMID: 33979636) identified 4 unrelated individuals with different biallelic protein-truncating variants in the PGM2L1 gene. All had severe GDD/ID. Other features that reach the threshold for inclusion on the relevant panels (observed in at least 3 cases) are epilepsy and early obesity (99th centile at ages 2 to 3). Some functional data included.
Intellectual disability v3.1218 PGM2L1 Arina Puzriakova Gene: pgm2l1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1217 TCF7L2 Konstantinos Varvagiannis reviewed gene: TCF7L2: Rating: AMBER; Mode of pathogenicity: None; Publications: 34003604; Phenotypes: Global developmental delay, Intellectual disability, Autism, Attention deficit hyperactivity disorder, Myopia, Abnormality of skeletal system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1217 PIDD1 Konstantinos Varvagiannis changed review comment from: There is enough evidence to include this gene in the current panel with green rating.

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

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

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

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

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

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

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

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

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

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

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

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature, Other; to: There is enough evidence to include this gene in the current panel with green rating.

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

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

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

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

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

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

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

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

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

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

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

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature, Other
Intellectual disability v3.1217 PIDD1 Konstantinos Varvagiannis gene: PIDD1 was added
gene: PIDD1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum
Penetrance for gene: PIDD1 were set to Complete
Review for gene: PIDD1 was set to GREEN
Added comment: There is enough evidence to include this gene in the current panel with green rating.

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

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

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

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

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

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

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

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

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

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

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

Overall the gene appears to be relevant for the epilepsy panel, panels for gyration and/or corpus callosum anomalies etc.
Sources: Literature, Other
Intellectual disability v3.1217 RFX7 Ivone Leong Phenotypes for gene: RFX7 were changed from ID, ASD, ADHD to Intellectual disability, MONDO:0001071, autism spectrum disorder, MONDO:0005258, attention deficit-hyperactivity disorder, MONDO:0007743
Intellectual disability v3.1216 ZC3H14 Ivone Leong commented on gene: ZC3H14
Intellectual disability v3.1216 AP1G1 Zornitza Stark gene: AP1G1 was added
gene: AP1G1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AP1G1 were set to 34102099
Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy
Review for gene: AP1G1 was set to GREEN
gene: AP1G1 was marked as current diagnostic
Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants.

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

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

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

GREEN for mono-allelic, AMBER for bi-allelic.
Sources: Literature
Intellectual disability v3.1216 TP73 Zornitza Stark edited their review of gene: TP73: Added comment: New publication adds further evidence for gene-disease association, PMID 34077761:

- Seven individuals from five unrelated families homozygous for TP73 variants (includes 1x large deletion, 1x splice variant, 1x frameshift and 2x nonsense variants) and cortical malformations/ID
- In vitro ciliogenesis experiments demonstrated that epithelial cells from TP73 variant carriers had reduced number of ciliated cells and shortened cilia resulting in abnormal ciliary clearance of the airways compared to healthy controls; Changed rating: GREEN; Changed publications to: 31130284, 34077761
Intellectual disability v3.1216 CLCN3 Zornitza Stark gene: CLCN3 was added
gene: CLCN3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CLCN3 was set to Other
Review for gene: CLCN3 was set to GREEN
gene: CLCN3 was marked as current diagnostic
Added comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.

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

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

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

Both loss and gain of function in this gene resulted in the same phenotype.

Green for mono-allelic variants, Amber/Red for bi-allelic.
Sources: Literature
Intellectual disability v3.1216 TNPO2 Zornitza Stark reviewed gene: TNPO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34314705; Phenotypes: Intellectual disability, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1216 ANK2 Zornitza Stark gene: ANK2 was added
gene: ANK2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 22542183; 25363768; 27479843; 28554332; 30564305; 30755392; 31981491; 33004838; 33057194
Phenotypes for gene: ANK2 were set to Complex neurodevelopmental disorder, MONDO:0100038
Review for gene: ANK2 was set to GREEN
gene: ANK2 was marked as current diagnostic
Added comment: Note link with cardiac abnormalities such as LongQT is DISPUTED.

However, more than 10 unrelated individuals reported with neurodevelopmental phenotype, comprising autism/ID and de novo truncating variants, in addition to many other individuals as part of large NDD cohorts. This association has been assessed as DEFINITIVE by ClinGen.
Sources: Literature
Intellectual disability v3.1216 LINGO4 Zornitza Stark gene: LINGO4 was added
gene: LINGO4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LINGO4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LINGO4 were set to 33098801
Phenotypes for gene: LINGO4 were set to Intellectual disability; speech disorder
Review for gene: LINGO4 was set to GREEN
gene: LINGO4 was marked as current diagnostic
Added comment: 3 unrelated individuals reported with bi-allelic variants in this gene and neurodevelopmental disorder:
1 x individual compound heterozygous for 2x missense variants:
c.679C>A; c.1262G>A p.Leu227Met; p.Arg421Gln. Phenotype: infancy-onset
generalized dystonia; ID, speech disorder

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

1 x individual homozygous for missense variant: c.1673G>A p.Ser558Asn Phenotype: ID, speech disorder
Sources: Literature
Intellectual disability v3.1216 IMPDH2 Zornitza Stark gene: IMPDH2 was added
gene: IMPDH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IMPDH2 were set to 33098801
Phenotypes for gene: IMPDH2 were set to Neurodevelopmental disorder with dystonia
Review for gene: IMPDH2 was set to GREEN
Added comment: 6 unrelated individuals
1x individual in a dystonia cohort index case with infancy-onset dystonia and other neurological manifestations with a de-novo missense variant, c.338G>A (p.Gly113Glu) in IMPDH2, predicted to disrupt an invariant residue within the cystathionine-β-synthase (CBS) domain pair of the encoded protein.
IMPDH2 encodes IMPDH2, a key enzyme in the purine biosynthetic pathway, expressed throughout the brain and not linked previously to any human Mendelian condition.
1x individual with a de-novo substitution, c.337G>A (p.Gly113Arg), was found in in-house whole-exome sequencing data from 500 individuals with neurodevelopmental disorders. Through GeneMatcher, de novo variants identified:
3 x missense: c.729G>C (p.Gln243His), c.619G>C (p.Gly207Arg), and c.619G>A (p.Gly207Arg)
1 x deletion: c.478_480delTCC (p.Ser160del)
The six variants were predicted to be deleterious and none of them seen in control databases. All affected conserved amino acids and resided in and around the cystathionine-β-synthase domain pair.
The described variants are situated in and around the CBS domain pair, a regulatory element in which clustering of pathogenic missense variants has already been shown for the homologue of IMPDH2, IMPDH1.

All individuals shared similar neurodevelopmental phenotypes. Apart from the dystonia cohort index case, one participant had evidence of dystonic posturing.

Modelling of the variants on 3D protein structures revealed spatial clustering near specific functional sites, predicted to result in deregulation of IMPDH2 activity. Additionally, thermal-shift assays showed that the c.619G>A (p.Gly207Arg) variant, identified as within the CBS domain pair, and c.729G>C (p.Gln243His), which is in close vicinity, affected the stability or folding behaviour of IMPDH2.
Sources: Literature
Intellectual disability v3.1216 KIF1A Arina Puzriakova Added comment: Comment on mode of inheritance: ID is most prominent in patients with NESCAV syndrome (MIM# 614255) caused by monoallelic variants in this gene. KIF1A is also associated HSP type 30 (MIM# 610357) which can be inherited recessively or dominantly - however, mostly only the dominant form has been shown to involve some variable cognitive impairment. Of the 4 families reported to date with recessive HSP (PMID: 21487076; 22258533; 28332297), only 1 presented with ID (PMID: 28332297).

Therefore, MOI should remain at 'monoallelic' only on this panel.
Intellectual disability v3.1216 KIF1A Arina Puzriakova Mode of inheritance for gene: KIF1A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1215 KIF1A Arina Puzriakova Phenotypes for gene: KIF1A were changed from Mental Retardation, Dominant; Spastic paraplegia 30, autosomal recessive, 610357Neuropathy, hereditary sensory, type IIC, 614213Mental retardation, autosomal dominant 9, 614255; MENTAL RETARDATION, AUTOSOMAL DOMINANT 9 to NESCAV syndrome, OMIM:614255; Spastic paraplegia 30, autosomal dominant, OMIM:610357
Intellectual disability v3.1214 COG5 Ivone Leong Tag Q3_21_MOI tag was added to gene: COG5.
Intellectual disability v3.1214 COG5 Ivone Leong changed review comment from: MOI should be changed from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BIALLELIC, autosomal or pseudoautosomal".; to: MOI should be changed from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BIALLELIC, autosomal or pseudoautosomal".
Intellectual disability v3.1214 COG5 Ivone Leong reviewed gene: COG5: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1214 COG4 Arina Puzriakova Publications for gene: COG4 were set to 25529582
Intellectual disability v3.1213 COG4 Arina Puzriakova Added comment: Comment on mode of inheritance: Early developmental delay (speech and motor) can be a feature of Saul-Wilson syndrome (monoallelic inheritance), however cognition is normal. Therefore, the monoallelic form is not pertinent to this panel and the MOI should remain as biallelic only which is associated with CDG-IIj, including psychomotor retardation.
Intellectual disability v3.1213 COG4 Arina Puzriakova Mode of inheritance for gene: COG4 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1212 COG4 Arina Puzriakova Tag for-review was removed from gene: COG4.
Intellectual disability v3.1212 MYCN Ivone Leong Publications for gene: MYCN were set to 21224895; 8470948
Intellectual disability v3.1211 MYCN Ivone Leong Phenotypes for gene: MYCN were changed from Feingold syndrome, 164280; FEINGOLD SYNDROME TYPE 1 to Feingold syndrome 1, OMIM:164280
Intellectual disability v3.1210 MYCN Ivone Leong Publications for gene: MYCN were set to
Intellectual disability v3.1209 PTPN4 Ivone Leong Classified gene: PTPN4 as Amber List (moderate evidence)
Intellectual disability v3.1209 PTPN4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Based on the expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1209 PTPN4 Ivone Leong Gene: ptpn4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1209 PTPN4 Ivone Leong Classified gene: PTPN4 as Amber List (moderate evidence)
Intellectual disability v3.1209 PTPN4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Based on the expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1209 PTPN4 Ivone Leong Gene: ptpn4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1208 PTPN4 Ivone Leong Tag Q3_21_rating tag was added to gene: PTPN4.
Intellectual disability v3.1208 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685 to Encephalopathy, progressive, with or without lipodystrophy, OMIM:615924; Lipodystrophy, congenital generalized, type 2, OMIM:269700
Intellectual disability v3.1207 BSCL2 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: BSCL2.
Intellectual disability v3.1207 BSCL2 Arina Puzriakova Added comment: Comment on mode of inheritance: Monoallelic variants lead to a motor neuropathy (MIM# 619112) or spastic paraplegia (MIM# 270685) presentation, both characterised by motor symptoms, but neither are associated with any cognitive deficits. On the other hand, biallelic variants cause encephalopathy (MIM# 615924) or generalised lipodystrophy (MIM# 269700) which do include cognitive decline and intellectual impairment, respectively.

Therefore, the MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only at the next GMS panel review.
Intellectual disability v3.1207 BSCL2 Arina Puzriakova Mode of inheritance for gene: BSCL2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1206 DLL1 Arina Puzriakova Phenotypes for gene: DLL1 were changed from Global developmental delay; Intellectual disability; Morphological abnormality of the central nervous system; Seizures; Behavioral abnormality; Autism; Scoliosis to Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures, OMIM:618709
Intellectual disability v3.1205 BMPR1B Arina Puzriakova Phenotypes for gene: BMPR1B were changed from Brachydactyly, type A2, 112600; Chrondrodysplasia, acromesomelic, with genital anomalies, 609441 to Acromesomelic dysplasia, Demirhan type, OMIM:609441; Brachydactyly, type A1, D, OMIM:616849; Brachydactyly, type A2, OMIM:112600
Intellectual disability v3.1204 BMPR1B Arina Puzriakova Mode of inheritance for gene: BMPR1B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1203 PTPN4 Ivone Leong Phenotypes for gene: PTPN4 were changed from Intellectual disability to Intellectual disability, MONDO:0001071
Intellectual disability v3.1202 PTPN4 Ivone Leong Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Intellectual disability v3.1201 SYNCRIP Konstantinos Varvagiannis reviewed gene: SYNCRIP: Rating: AMBER; Mode of pathogenicity: None; Publications: 34157790, 30504930, 27479843, 23020937; Phenotypes: Global developmental delay, Intellectual disability, Autism, Myoclonic atonic seizures, Abnormality of nervous system morphology; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1201 CAMK4 Konstantinos Varvagiannis gene: CAMK4 was added
gene: CAMK4 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Penetrance for gene: CAMK4 were set to Complete
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

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

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

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

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

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

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

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

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

---

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

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

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

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

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

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

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

----

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

----

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

----

There is no associated phenotype in OMIM, G2P, PanelApp AUS.

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

----

Please consider inclusion in other relevant panels.
Sources: Literature, Other
Intellectual disability v3.1201 ATP9A Konstantinos Varvagiannis edited their review of gene: ATP9A: Changed publications to: http://dx.doi.org/10.1136/jmedgenet-2021-107843
Intellectual disability v3.1201 ATP9A Konstantinos Varvagiannis gene: ATP9A was added
gene: ATP9A was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATP9A were set to Global developmental delay; Intellectual disability; Postnatal microcephaly; Failure to thrive; Abnormality of the abdomen
Penetrance for gene: ATP9A were set to Complete
Review for gene: ATP9A was set to AMBER
Added comment: Vogt, Verheyen et al (2021 - http://dx.doi.org/10.1136/jmedgenet-2021-107843) report 3 affected individuals from 2 unrelated consanguineous families.

Features included DD, variable ID (Fam1: sib1-mild, sib2-possible, Fam2: severe), postnatal microcephaly (-2.33 to -3.58 SD), failure to thrive as well as gastrointestinal symptoms (nausea, vomiting, GE reflux).

These subjects were homozygous for pLoF ATP9A variants private to each family.

Previous investigations incl. karyotype, aCGH and transferrin electophoresis (CDGs) and were unremarkable.

Diagnosis was made by exome sequencing and homozygosity mapping. Affected sibs from the first family were homozygous for a stopgain variant [NM_006045.3:c.868C>Τ / p.(Arg290*)]. The subject from the second family was homozygous for a variant affecting the consensus (donor) splice site [c.642+1G>A - same RefSeq]. Both variants were absent from gnomAD. Sanger sequencing was used to confirm variants, carrier status of the parents and unaffected sibs in both families.

Sequencing of cDNA from the individual homozygous for the splicing variant demonstrated skipping of exon 7 with the variant likely leading to frameshift and introduction of a premature stop codon.

qPCR in dermal fibroblasts from affected individuals from both families revealed expression downregulation of ATP9A (14% and 4% respectively for the stopgain and splice variant). Study at the protein level was not possible due to absence of antibody against endogenous ATP9A.

ATP9A encodes ATPase phospholipid transporting 9A (similarly to ATP9B) belonging to the subclass 2 of the P4-ATPase family. As the authors comment, the protein is mainly expressed in the brain although the precise function or subcellular distribution of endogenous ATP9A are unknown.

A previous study showed that overexpressed ATP9A in HeLa cells localizes to early/recycling endosomes and the trans-Golgi network, being required for endocytic recycling of the transferrin receptor to the plasma membrane. ATP9A (in complex with DOP1B and MON2) functionally interacts with the SNX3-retromer. A previous ATP9A knockdown cell line suggested dysregulation of >100 genes with ARPC3 (actin-related protein 2/3 complex subunit 3) being strongly upregulated.

Overall ATP9A appears to have a role in endosome trafficking pathways as well as to inhibit secretion of exosomes at the plasma membrane likely due to alteration of the actin cytoskeleton.

In line with the role of APT9A in early/recycling endosomes and identified interactions, the authors demonstrated overexpression of ARPC3 and SNX3. Study of genes encoding other known interacting proteins was not possible due to poor expression in fibroblasts.

As the authors note, mutations in genes encoding proteins of the Golgi and endosomal trafficking are important for brain development and have been associated with postnatal microcephaly.

In OMIM, G2P, SysID there is no associated phenotype.

The gene is included in the ID panel of PanelApp AUS with amber rating.
Sources: Literature, Other
Intellectual disability v3.1201 ZDHHC9 Ivone Leong Phenotypes for gene: ZDHHC9 were changed from Mental retardation, X-linked syndromic, Raymond type, 300799; MENTAL RETARDATION SYNDROMIC X-LINKED ZDHHC9-RELATED (MRXSZ) to Mental retardation, X-linked syndromic, Raymond type, OMIM:300799
Intellectual disability v3.1200 CEP85L Sarah Leigh Tag Q3_21_rating tag was added to gene: CEP85L.
Intellectual disability v3.1200 CEP85L Sarah Leigh edited their review of gene: CEP85L: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least nine variants reported in nine unrelated families. PMID 32097630 comments that - the CEP85L gene as a whole is tolerant to loss of function and to missense variation. However, the 4 missense variants that have been identified in patients affect a 15-aa region of the protein that is highly intolerant to missense variation, the splicing and start-loss variants are predicted to produce a shortened protein that excludes the same 15-aa region. It is speculated that variants in this constrained region, may act through a dominant-negative mechanism.
Intellectual disability was apparent in eight of the families studied, ranging from mild (three families) to moderate (five families).
Supportive studies were also presented (PMID 32097630, 32097629).; Changed rating: GREEN
Intellectual disability v3.1200 CEP85L Sarah Leigh Classified gene: CEP85L as Amber List (moderate evidence)
Intellectual disability v3.1200 CEP85L 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 v3.1200 CEP85L Sarah Leigh Gene: cep85l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1199 CEP85L Sarah Leigh Phenotypes for gene: CEP85L were changed from Intellectual disability; epilepsy, lissencephaly to Lissencephaly 10, OMIM:618873; Lissencephaly 10, MONDO:0030031
Intellectual disability v3.1198 DPYSL5 Ivone Leong Tag Q3_21_rating tag was added to gene: DPYSL5.
Intellectual disability v3.1198 DPYSL5 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM.

PMID: 33894126. 10 individuals (2 of whom are related). 7/7 had severe ID, 9/9 DD and hypotonia, 3/6 ataxia, 3/10 seizures, 6/7 cerebellar hypoplasia and 7/10 corpus callosum agenesis.

Based on literature and expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM.

PMID: 33894126. 10 individuals (2 of whom are related). 7/7 had severe ID, 9/9 DD and hypotonia, 3/6 ataxia, 3/10 seizures, 6/7 cerebellar hypoplasia and 7/10 corpus callosum agenesis. Age range from 2.5 years to 33 years.

Based on literature and expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1198 DPYSL5 Ivone Leong Classified gene: DPYSL5 as Amber List (moderate evidence)
Intellectual disability v3.1198 DPYSL5 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 (probable) but not in OMIM.

PMID: 33894126. 10 individuals (2 of whom are related). 7/7 had severe ID, 9/9 DD and hypotonia, 3/6 ataxia, 3/10 seizures, 6/7 cerebellar hypoplasia and 7/10 corpus callosum agenesis.

Based on literature and expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1198 DPYSL5 Ivone Leong Gene: dpysl5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1197 CHD5 Ivone Leong Tag Q3_21_rating tag was added to gene: CHD5.
Intellectual disability v3.1197 CHD5 Ivone Leong Classified gene: CHD5 as Amber List (moderate evidence)
Intellectual disability v3.1197 CHD5 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 (possible) but not in OMIM.

PMID: 33944996. Age ranged from 3 years - 22 years. 9/14 individuals had ID (only 6 of 9 patients were assessed for severity with 2 moderate ID and 4 severe cases). 10/16 individuals had epilepsy. 7/14 had hypotonia and 3/7 had craniosynostosis. 16 different variants were identified (11 missense, 1 frameshift, 2 nonsense and 2 splice site variants).

There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1197 CHD5 Ivone Leong Gene: chd5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1196 CHD5 Ivone Leong Phenotypes for gene: CHD5 were changed from Intellectual disability; Epilepsy to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1195 CEP85L Rachel Challis gene: CEP85L was added
gene: CEP85L was added to Intellectual disability. Sources: NHS GMS
Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CEP85L were set to 32097629; 32097630
Phenotypes for gene: CEP85L were set to Intellectual disability; epilepsy, lissencephaly
Penetrance for gene: CEP85L were set to unknown
Review for gene: CEP85L was set to GREEN
gene: CEP85L was marked as current diagnostic
Added comment: Recommend adding as Green gene to GMS - R29 Intellectual disability panel.

Monoallelic missense and loss of function variants in CEP85L are associated with Lissencephaly (OMIM 618873). Over 10 unrelated families have been described with de novo and inherited rare variants in CEP85L. Functional work in cell lines and knockdown of Cep85l in mice confirms the role of CEP85L in neuronal migration.
PMID: 32097629
PMID: 32097630
Sources: NHS GMS
Intellectual disability v3.1195 PCDHGC4 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO (15/7/2021). At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Intellectual disability v3.1195 PCDHGC4 Sarah Leigh Classified gene: PCDHGC4 as Amber List (moderate evidence)
Intellectual disability v3.1195 PCDHGC4 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 v3.1195 PCDHGC4 Sarah Leigh Gene: pcdhgc4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1194 PCDHGC4 Sarah Leigh gene: PCDHGC4 was added
gene: PCDHGC4 was added to Intellectual disability. Sources: Literature
Q3_21_rating tags were added to gene: PCDHGC4.
Mode of inheritance for gene: PCDHGC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDHGC4 were set to 34244665
Phenotypes for gene: PCDHGC4 were set to neurodevelopmental syndrome
Review for gene: PCDHGC4 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Intellectual disability v3.1193 ATXN2L Ivone Leong Tag watchlist tag was added to gene: ATXN2L.
Intellectual disability v3.1193 ATXN2L Ivone Leong Classified gene: ATXN2L as Amber List (moderate evidence)
Intellectual disability v3.1193 ATXN2L Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not asssociated with a phenotype in OMIM or Gene2Phenotype. There is not enough evidence to support a gene-disease association. This gene has been given a Amber rating.
Intellectual disability v3.1193 ATXN2L Ivone Leong Gene: atxn2l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1192 EPHA7 Ivone Leong Tag watchlist tag was added to gene: EPHA7.
Intellectual disability v3.1192 EPHA7 Ivone Leong Classified gene: EPHA7 as Amber List (moderate evidence)
Intellectual disability v3.1192 EPHA7 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. This gene has been given an Amber rating based on expert review.
Intellectual disability v3.1192 EPHA7 Ivone Leong Gene: epha7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1191 EPHA7 Ivone Leong Phenotypes for gene: EPHA7 were changed from Global developmental delay; Intellectual disability; Delayed speech and language development; Behavioral abnormality to Global developmental delay; Intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality
Intellectual disability v3.1190 ERGIC3 Ivone Leong Tag watchlist tag was added to gene: ERGIC3.
Intellectual disability v3.1190 ERGIC3 Ivone Leong Classified gene: ERGIC3 as Amber List (moderate evidence)
Intellectual disability v3.1190 ERGIC3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not asssociated with a phenotype in OMIM or Gene2Phenotype. There is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1190 ERGIC3 Ivone Leong Gene: ergic3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1189 ERGIC3 Ivone Leong Phenotypes for gene: ERGIC3 were changed from Intellectual disability to Intellectual disability, MONDO:0001071
Intellectual disability v3.1188 HEATR5B Ivone Leong Classified gene: HEATR5B as Amber List (moderate evidence)
Intellectual disability v3.1188 HEATR5B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1188 HEATR5B Ivone Leong Gene: heatr5b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1187 HEATR5B Ivone Leong Tag watchlist tag was added to gene: HEATR5B.
Intellectual disability v3.1187 HEATR5B Ivone Leong Phenotypes for gene: HEATR5B were changed from pontocerebellar hypoplasia; intellectual disability; seizures to pontocerebellar hypoplasia, MONDO:0020135; intellectual disability, MONDO:0001071; seizures
Intellectual disability v3.1186 JPH3 Ivone Leong Classified gene: JPH3 as Red List (low evidence)
Intellectual disability v3.1186 JPH3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is asssociated with a phenotype in OMIM but not Gene2Phenotype. As there is only one case there is not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Intellectual disability v3.1186 JPH3 Ivone Leong Gene: jph3 has been classified as Red List (Low Evidence).
Intellectual disability v3.1185 KIF1B Ivone Leong Classified gene: KIF1B as Red List (low evidence)
Intellectual disability v3.1185 KIF1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is asssociated with a phenotype in OMIM but not Gene2Phenotype. As there is only one case there is not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Intellectual disability v3.1185 KIF1B Ivone Leong Gene: kif1b has been classified as Red List (Low Evidence).
Intellectual disability v3.1184 KIF1B Ivone Leong Phenotypes for gene: KIF1B were changed from Hypotonia; coloboma; hypoplasia of the corpus callosum; severe neurodevelopmental delay to Hypotonia; coloboma, MONDO:0001476; hypoplasia of the corpus callosum; severe neurodevelopmental delay
Intellectual disability v3.1183 SAMD9L Ivone Leong Classified gene: SAMD9L as Red List (low evidence)
Intellectual disability v3.1183 SAMD9L 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 and Gene2Phenotype, but nothing related to ID. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red status.
Intellectual disability v3.1183 SAMD9L Ivone Leong Gene: samd9l has been classified as Red List (Low Evidence).
Intellectual disability v3.1182 SAMD9L Ivone Leong Phenotypes for gene: SAMD9L were changed from Intellectual disability to Intellectual disability, MONDO:0001071
Intellectual disability v3.1181 SPTBN1 Sarah Leigh Classified gene: SPTBN1 as Amber List (moderate evidence)
Intellectual disability v3.1181 SPTBN1 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 v3.1181 SPTBN1 Sarah Leigh Gene: sptbn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1180 SPTBN1 Sarah Leigh gene: SPTBN1 was added
gene: SPTBN1 was added to Intellectual disability. Sources: Literature
Q3_21_rating tags were added to gene: SPTBN1.
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to 34211179
Phenotypes for gene: SPTBN1 were set to autosomal dominant neurodevelopmental syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO (as of 13/07/2021). At least 27 monoallelic variants reported in 29 individuals with neurodevelopmental abnormalities. Developmental delay was reported in 28/28 tested cases. Intellectual disabilty was reported in 21/24 tested cases (including severe in 5 cases, moderate to severe in 2 cases and moderate in 4 cases) and epilepsy/seizures was reported in 9/24 tested cases (including febrile seizures in 2 cases). Extensive supportive functional evidence was also reported (PMID 34211179).
Sources: Literature
Intellectual disability v3.1179 CAMK2A Ivone Leong Tag watchlist_moi tag was added to gene: CAMK2A.
Intellectual disability v3.1179 NAA20 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature; to: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 in this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature
Intellectual disability v3.1179 NAA20 Sarah Leigh Classified gene: NAA20 as Amber List (moderate evidence)
Intellectual disability v3.1179 NAA20 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be amber on this panel, based on two missense variants, which have supporting in silico and experimental evidence in cases with mild to severe intellectually disability (PMID 34230638).
Intellectual disability v3.1179 NAA20 Sarah Leigh Gene: naa20 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1178 NAA20 Sarah Leigh Added comment: Comment on phenotypes: Currently there is no phenotype associated with this gene in OMIM, Gen2Phen or MONDO (13/07/2021).
Intellectual disability v3.1178 NAA20 Sarah Leigh Phenotypes for gene: NAA20 were changed from autosomal recessive developmental delay, intellectual disability, and microcephaly to autosomal recessive developmental delay, intellectual disability, and microcephaly
Intellectual disability v3.1177 NAA20 Sarah Leigh gene: NAA20 was added
gene: NAA20 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NAA20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA20 were set to 34230638
Phenotypes for gene: NAA20 were set to autosomal recessive developmental delay, intellectual disability, and microcephaly
Review for gene: NAA20 was set to AMBER
Added comment: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature
Intellectual disability v3.1176 CAMK2A Ivone Leong Added comment: Comment on phenotypes: Previously:
Intellectual disability
Intellectual disability v3.1176 CAMK2A Ivone Leong Phenotypes for gene: CAMK2A were changed from Intellectual disability to Mental retardation, autosomal dominant 53, OMIM:617798; ?Mental retardation, autosomal recessive 63, OMIM:618095
Intellectual disability v3.1175 CAMK2A Ivone Leong Added comment: Comment on publications: PMID:29784083. 2 siblings born from consanguineous parents from Jordan with homozygous missense variant. Both had severe ID.
Intellectual disability v3.1175 CAMK2A Ivone Leong Publications for gene: CAMK2A were set to 26350204; 29100089
Intellectual disability v3.1174 MYT1 Ivone Leong Classified gene: MYT1 as Red List (low evidence)
Intellectual disability v3.1174 MYT1 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 in OMIM. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Intellectual disability v3.1174 MYT1 Ivone Leong Gene: myt1 has been classified as Red List (Low Evidence).
Intellectual disability v3.1173 MYT1 Ivone Leong Added comment: Comment on publications: PMID:18341605. A case with de novo subtelomeric deletion on chromosome 20 containing MYT1 and PCMTD2. Both genes affect myelination and neural differentiation.

PMID:33710394. Authors also discuss that variants in MYT1 have been identified in patients with oculo-auriculo-vertebral spectrum (OAVS) who have normal intelligence.
Intellectual disability v3.1173 MYT1 Ivone Leong Publications for gene: MYT1 were set to 33710394
Intellectual disability v3.1172 MYT1 Ivone Leong Phenotypes for gene: MYT1 were changed from Intellectual disability to Intellectual disability, MONDO:0001071
Intellectual disability v3.1171 SRCAP Ivone Leong Publications for gene: SRCAP were set to
Intellectual disability v3.1170 ASCC3 Ivone Leong Classified gene: ASCC3 as Amber List (moderate evidence)
Intellectual disability v3.1170 ASCC3 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. New publication (https://doi.org/10.1016/j.xhgg.2021.100024) describing 11 individuals from 7 unrelated families (1 family was originally described in PMID: 21937992 and had mild ID). Patients had phenotypes ranging from mild to severe developmental dealys. As ID is not the prominant phenotype, this gene has been given an Amber rating.
Intellectual disability v3.1170 ASCC3 Ivone Leong Gene: ascc3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1169 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Frontometaphyseal dysplasia, 305620Heterotopia, periventricular, ED variant, 300537FG syndrome 2, 300321Cardiac valvular dysplasia, X-linked, 314400Terminal osseous dysplasia, 300244Congenital short bowel syndrome, 300048; EPILEPTIC ENCEPHALOPATHY to Heterotopia, periventricular, 1, OMIM:300049; Otopalatodigital syndrome, type II, OMIM:304120; ?FG syndrome 2, OMIM:300321
Intellectual disability v3.1168 ASCC3 Ivone Leong Publications for gene: ASCC3 were set to 21937992; 26350204
Intellectual disability v3.1167 ACSL4 Ivone Leong reviewed gene: ACSL4: Rating: ; Mode of pathogenicity: None; Publications: 12525535, 11889465; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1167 ACSL4 Ivone Leong Deleted their review
Intellectual disability v3.1167 ACSL4 Ivone Leong changed review comment from: ACSL4 is said to be X-linked dominant in OMIM.

PMID: 12525535 - a family with 4 affected males, 1 unaffected male, 2 carrier females and 1 non-carrier female. All affected males full scale IQ (FSIQ) ranged from 43-71, unaffected male FSIQ is 116, carrier females ranged from 74-83 and non-carrier female is 133. All carrier females showed 100% skewed inactivation.

PMID: 11889465 - Family MRX63, all carrier females showed complete skewed X-inactivation. All affected males showed non-specific, non-progressive mental deficiency (moderate - severe). Carrier females showed highly variable cognitive capacities (normal to moderate).

Based on the available evidence the MOI should be 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)".; to: ACSL4 is said to be X-linked dominant in OMIM.

PMID: 12525535 - a family with 4 affected males, 1 unaffected male, 2 carrier females and 1 non-carrier female. All affected males full scale IQ (FSIQ) ranged from 43-71, unaffected male FSIQ is 116, carrier females ranged from 74-83 and non-carrier female is 133. All carrier females showed 100% skewed inactivation.

PMID: 11889465 - Family MRX63, all carrier females showed complete skewed X-inactivation. All affected males showed non-specific, non-progressive mental deficiency (moderate - severe). Carrier females showed highly variable cognitive capacities (normal to moderate).

As there are only 2 cases where carrier females have a phenotype, the MOI should be kept as "X-LINKED: hemizygous mutation in males, biallelic mutations in females".
Intellectual disability v3.1167 HID1 Zornitza Stark gene: HID1 was added
gene: HID1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HID1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HID1 were set to 33999436
Phenotypes for gene: HID1 were set to Syndromic infantile encephalopathy; Hypopituitarism
Review for gene: HID1 was set to GREEN
Added comment: 7 individuals from 6 unrelated families reported. Clinical features included: hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy.
Sources: Literature
Intellectual disability v3.1167 KIF1B Zornitza Stark gene: KIF1B was added
gene: KIF1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF1B were set to 33710394
Phenotypes for gene: KIF1B were set to Hypotonia; coloboma; hypoplasia of the corpus callosum; severe neurodevelopmental delay
Review for gene: KIF1B was set to RED
Added comment: Compound heterozygous missense variants reported in a woman with severe hypotonia, hypsarrhythmia, coloboma, hypoplasia of corpus callosum, severe neurodevelopmental delay.
Sources: Literature
Intellectual disability v3.1167 JPH3 Zornitza Stark gene: JPH3 was added
gene: JPH3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JPH3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH3 were set to 33824468
Phenotypes for gene: JPH3 were set to Intellectual disability; dystonia
Review for gene: JPH3 was set to RED
Added comment: One homozygous truncating variant (NM_020655.4: c.1740dup; p.(Val581Argfs*137)) found in a female individual affected with neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. No functional work.

STRs in this gene are associated with HD-like disorder.
Sources: Literature
Intellectual disability v3.1167 ERGIC3 Zornitza Stark gene: ERGIC3 was added
gene: ERGIC3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ERGIC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC3 were set to 33710394; 31585110
Phenotypes for gene: ERGIC3 were set to Intellectual disability
Review for gene: ERGIC3 was set to AMBER
Added comment: PMID: 33710394 - two homozygous sibs with mild ID, a novel canonical splice (c.717+1G>A). Absent in gnomAD, no splice studies. Classed as a VUS.

PMID: 31585110 - 1 hom (p.Gln233Argfs*10) in a male 8yo with Growth retardation, Microcephaly, Learning disability, Facial dysmorphism, Abnormal pigmentation.
Sources: Literature
Intellectual disability v3.1167 ZC3H14 Zornitza Stark reviewed gene: ZC3H14: Rating: AMBER; Mode of pathogenicity: None; Publications: 21734151, 33710394, 28666327; Phenotypes: Mental retardation, autosomal recessive 56 MIM#617125; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1167 MYT1 Zornitza Stark gene: MYT1 was added
gene: MYT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MYT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYT1 were set to 33710394
Phenotypes for gene: MYT1 were set to Intellectual disability
Review for gene: MYT1 was set to RED
Added comment: Missense variant reported de novo in a patient with mild ID reported in a cohort study. Patient also had a COL9A2 variant and skeletal features. Authors referred to it as an extended phenotype and dual diagnosis.
Sources: Literature
Intellectual disability v3.1167 ATP1A2 Zornitza Stark changed review comment from: Although some of the symptoms of this condition are episodic, intellectual disability is a recognised feature.; to: Alternating hemiplegia: Although some of the symptoms of this condition are episodic, intellectual disability is a recognised feature.
Intellectual disability v3.1167 ATP1A2 Zornitza Stark edited their review of gene: ATP1A2: Added comment: PMID 33880529: six individuals with de novo missense variants reported and DD/EE/PMG.; Changed publications to: 33880529; Changed phenotypes to: Alternating hemiplegia of childhood 1, MIM# 104290, Developmental and epileptic encephalopathy
Intellectual disability v3.1167 HEATR5B Zornitza Stark gene: HEATR5B was added
gene: HEATR5B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to 33824466
Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia; intellectual disability; seizures
Review for gene: HEATR5B was set to AMBER
Added comment: Four affected children from two families presenting with pontocerebellar hypoplasiawith neonatal seizures, severe ID and motor delay. Two homozygous splice variants were reported (c.5051–1G>A and c.5050+4A>G) in intron 31 of HEATR5B gene. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. Homozygous knockout mice were not viable
Sources: Literature
Intellectual disability v3.1167 RING1 Eleanor Williams gene: RING1 was added
gene: RING1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RING1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RING1 were set to 29386386
Phenotypes for gene: RING1 were set to microcephaly; intellectual disability
Review for gene: RING1 was set to RED
Added comment: Not associated with any phenotype in OMIM.

PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Early motor and language development were normal but were delayed after the first year of life. Cognitive testing showed a verbal IQ of 55 and a visual performance IQ of 63. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13 which falls into the severe microcephaly category. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature
Intellectual disability v3.1166 PPP1R21 Ivone Leong Added comment: Comment on phenotypes: Previously:
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 v3.1166 PPP1R21 Ivone Leong 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 to Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities, OMIM:619383
Intellectual disability v3.1165 NTNG2 Ivone Leong Phenotypes for gene: NTNG2 were changed from Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Microcephaly; Seizures to Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia, OMIM:618718
Intellectual disability v3.1164 CUX2 Arina Puzriakova Tag Q3_21_NHS_review tag was added to gene: CUX2.
Intellectual disability v3.1164 CUX2 Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'Monoallelic... paternally imprinted (maternal allele expressed)' to 'Monoallelic... NOT imprinted', in line with Tracy Lester's recent review highlighting there is no evidence of imprinting in this gene.
Intellectual disability v3.1164 CUX2 Arina Puzriakova Mode of inheritance for gene: CUX2 was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1163 ATP1A3 Zornitza Stark edited their review of gene: ATP1A3: Changed phenotypes to: Developmental and epileptic encephalopathy
Intellectual disability v3.1163 ATP1A3 Zornitza Stark edited their review of gene: ATP1A3: Added comment: Sixteen individuals reported with DD/EE.; Changed publications to: 33880529; Changed phenotypes to: Alternating hemiplegia of childhood 2, MIM#614820, Developmental and epileptic encephalopathy
Intellectual disability v3.1163 SAMD9L Zornitza Stark gene: SAMD9L was added
gene: SAMD9L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SAMD9L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD9L were set to 33710394
Phenotypes for gene: SAMD9L were set to Intellectual disability
Review for gene: SAMD9L was set to RED
Added comment: Missense variant reported de novo in a patient with moderate ID, in a large cohort study. Authors described it as a phenotype expansion as ataxia-pancytopenia not found in that patient.
Sources: Literature
Intellectual disability v3.1163 RFX4 Zornitza Stark gene: RFX4 was added
gene: RFX4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RFX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX4 were set to 33658631
Phenotypes for gene: RFX4 were set to ID, ASD, ADHD
Review for gene: RFX4 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability v3.1163 RFX3 Zornitza Stark gene: RFX3 was added
gene: RFX3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RFX3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX3 were set to 33658631
Phenotypes for gene: RFX3 were set to ID, ASD, ADHD
Review for gene: RFX3 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability v3.1163 RFX7 Zornitza Stark gene: RFX7 was added
gene: RFX7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RFX7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX7 were set to 33658631
Phenotypes for gene: RFX7 were set to ID, ASD, ADHD
Review for gene: RFX7 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability v3.1163 GNB2 Arina Puzriakova Classified gene: GNB2 as Amber List (moderate evidence)
Intellectual disability v3.1163 GNB2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1163 GNB2 Arina Puzriakova Gene: gnb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1162 GNB2 Arina Puzriakova gene: GNB2 was added
gene: GNB2 was added to Intellectual disability. Sources: Literature
Q3_21_rating tags were added to gene: GNB2.
Mode of inheritance for gene: GNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNB2 were set to 31698099; 33971351; 34183358
Phenotypes for gene: GNB2 were set to Intellectual disability
Review for gene: GNB2 was set to GREEN
Added comment: GNB2 is not yet associated with any phenotype in OMIM, but has a 'confirmed' disease confidence rating for 'GNB2-related developmental disorder (monoallelic)' in G2P.

At least 14 unrelated individuals with de novo monoallelic variants, including 5 recurrent variants in 13 individuals (PMIDs: 31698099; 33971351; 34183358). All patients (except one fetus owing to termination of pregnancy) have DD/ID of variable severity (mild to severe) which appeared to correlate with the variant each individual harboured. Other variable features include non-specific facial dysmorphism, hypotonia, and autistic behaviour.
Sources: Literature
Intellectual disability v3.1161 DNM1 Arina Puzriakova Phenotypes for gene: DNM1 were changed from EPILEPTIC ENCEPHALOPATHY to Developmental and epileptic encephalopathy 31, OMIM:616346
Intellectual disability v3.1160 ATP6V1A Arina Puzriakova Phenotypes for gene: ATP6V1A were changed from Epileptic encephalopathy, infantile or early childhood, 3 618012; Cutis laxa, autosomal recessive, type IID 617403 to Developmental and epileptic encephalopathy 93, OMIM:618012
Intellectual disability v3.1159 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from ATAXIA-TELANGIECTASIA; AT to Ataxia-telangiectasia, OMIM:208900
Intellectual disability v3.1158 ATP2C2 Eleanor Williams gene: ATP2C2 was added
gene: ATP2C2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP2C2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2C2 were set to 33864365; 28440294
Phenotypes for gene: ATP2C2 were set to language impairment, HP:0002463
Review for gene: ATP2C2 was set to RED
Added comment: PMID: 33864365 - Martinelli et al 2021 - report a family with a missense variant NM_001286527.2:c.304G>A, p.(Val102Met) in ATP2C2 in a father and two siblings with specific language impairment. However two other affected siblings did not have this variant. This variant was also reported by Chen et al. They found that the variant had a higher frequency in language cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). They postulate that variant is not sufficient on its own to cause a disorder but is a susceptibility factor which increases the risk for language impairment.

PMID: 28440294 - Chen et al 2017 - report 2 probands with severe learning impairment, and missense variants in ATP2C2 (NM_001286527: c.G304A:p.V102M and NM_001291454:exon21: c.C1936T:p.R646W).
Sources: Literature
Intellectual disability v3.1157 ACSL4 Ivone Leong Publications for gene: ACSL4 were set to
Intellectual disability v3.1156 ACSL4 Ivone Leong reviewed gene: ACSL4: Rating: ; Mode of pathogenicity: None; Publications: 12525535, 11889465; 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 v3.1156 ACSL4 Ivone Leong Tag Skewed X-inactivation tag was added to gene: ACSL4.
Intellectual disability v3.1156 ACSL4 Ivone Leong Phenotypes for gene: ACSL4 were changed from Mental retardation, X-linked 63, OMIM:300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR) to Mental retardation, X-linked 63, OMIM:300387; Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome, MONDO:0010263
Intellectual disability v3.1155 ACSL4 Ivone Leong Phenotypes for gene: ACSL4 were changed from Mental retardation, X-linked 63, 300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR) to Mental retardation, X-linked 63, OMIM:300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR)
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 Tag Q3_21_MOI tag was added to gene: ARHGEF9.
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 v3.1154 ARHGEF9 Arina Puzriakova Mode of inheritance for gene: ARHGEF9 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability 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 v3.1152 AR Arina Puzriakova Phenotypes for gene: AR were changed from SPINAL AND BULBAR MUSCULAR ATROPHY to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Intellectual disability v3.1151 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from Congenital disorder of glycosylation, type Ie, 608799; CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type Ie, OMIM:608799
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 v3.1150 FBXO31 Ivone Leong Tag watchlist was removed from gene: FBXO31.
Tag Q2_21_rating tag was added to gene: FBXO31.
Intellectual disability v3.1150 FBXO31 Ivone Leong Publications for gene: FBXO31 were set to 24623383; 32989326
Intellectual disability v3.1149 UFSP2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: UFSP2.
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 Tag watchlist tag was added to gene: JMJD1C.
Intellectual disability v3.1149 JMJD1C Arina Puzriakova Classified gene: JMJD1C as Amber List (moderate evidence)
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 v3.1149 JMJD1C Arina Puzriakova Gene: jmjd1c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1148 JMJD1C Arina Puzriakova Phenotypes for gene: JMJD1C were changed from Intellectual disability to Intellectual disability; Autism
Intellectual disability v3.1147 JMJD1C Arina Puzriakova Publications for gene: JMJD1C were set to 26181491; 32996679
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 v3.1146 KDM3B Ivone Leong Added comment: Comment on publications: PMID: 30929739. 8/16 patients had short stature (< -2.5 SD) and 9/15 had neonatal feeding difficulties. 5/16 had joint hypermobility, 4/17 had hearing loss.
Intellectual disability v3.1146 KDM3B Ivone Leong Publications for gene: KDM3B were set to 30929739
Intellectual disability v3.1145 KDM3B Ivone Leong Tag Q2_21_rating tag was added to gene: KDM3B.
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 Tag Q2_21_rating tag was added to gene: GEMIN5.
Intellectual disability v3.1145 GEMIN5 Arina Puzriakova Classified gene: GEMIN5 as Amber List (moderate evidence)
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 v3.1145 GEMIN5 Arina Puzriakova Gene: gemin5 has been classified as Amber List (Moderate Evidence).
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 Tag Q2_21_rating tag was added to gene: BCAS3.
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Classified gene: BCAS3 as Amber List (moderate evidence)
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 v3.1143 BCAS3 Arina Puzriakova Gene: bcas3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1142 CPE Arina Puzriakova Tag watchlist tag was added to gene: CPE.
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 Classified gene: CPE as Amber List (moderate evidence)
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 v3.1142 CPE Arina Puzriakova Gene: cpe has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1141 CPE Arina Puzriakova Phenotypes for gene: CPE were changed from Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326 to Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326
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 v3.1139 ALKBH8 Arina Puzriakova Phenotypes for gene: ALKBH8 were changed from Global developmental delay; Seizures; Intellectual disability to Intellectual developmental disorder, autosomal recessive 71, OMIM:618504
Intellectual disability v3.1138 SLC17A5 Arina Puzriakova Phenotypes for gene: SLC17A5 were changed from Salla disease, 604369Sialic acid storage disorder, infantile, 269920; SALLA DISEASE (SD) to Salla disease, OMIM:604369; Sialic acid storage disorder, infantile, OMIM:269920
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 v3.1136 RUBCN Arina Puzriakova Tag founder-effect tag was added to gene: RUBCN.
Intellectual disability v3.1136 RUBCN Arina Puzriakova Publications for gene: RUBCN were set to 20826435
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 v3.1134 POLR3B Arina Puzriakova Publications for gene: POLR3B were set to
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 v3.1133 POLR3B Arina Puzriakova Mode of inheritance for gene: POLR3B was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1132 POLR3B Arina Puzriakova Tag Q2_21_MOI tag was added to gene: POLR3B.
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 v3.1128 EIF3F Arina Puzriakova Phenotypes for gene: EIF3F were changed from Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment to Mental retardation, autosomal recessive 67, OMIM:618295
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 v3.1126 VPS41 Arina Puzriakova Entity copied from Childhood onset dystonia or chorea or related movement disorder v1.130
Intellectual disability v3.1126 VPS41 Arina Puzriakova gene: VPS41 was added
gene: VPS41 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: VPS41.
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683; 33764426; 33851776
Phenotypes for gene: VPS41 were set to Dystonia; Intellectual disability
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 Tag Q2_21_rating tag was added to gene: SIN3B.
Intellectual disability v3.1125 SIN3B Arina Puzriakova Classified gene: SIN3B as Amber List (moderate evidence)
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 v3.1125 SIN3B Arina Puzriakova Gene: sin3b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1124 EMC10 Arina Puzriakova Classified gene: EMC10 as Amber List (moderate evidence)
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 v3.1124 EMC10 Arina Puzriakova Gene: emc10 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1123 EMC10 Arina Puzriakova Tag Q2_21_rating tag was added to gene: EMC10.
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 v3.1123 EMC10 Arina Puzriakova Publications for gene: EMC10 were set to 32869858
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 CPE Zornitza Stark gene: CPE was added
gene: CPE was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CPE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPE were set to 26120850; 32936766
Phenotypes for gene: CPE were set to Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326
Review for gene: CPE was set to AMBER
Added comment: Four affected individuals from two unrelated families reported, bi-allelic LoF variants.
Sources: Literature
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 Classified gene: CAPN15 as Amber List (moderate evidence)
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 v3.1120 CAPN15 Arina Puzriakova Gene: capn15 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1119 CAPN15 Arina Puzriakova Tag Q2_21_rating tag was added to gene: CAPN15.
Intellectual disability v3.1119 CAPN15 Arina Puzriakova Phenotypes for gene: CAPN15 were changed from Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318 to Oculogastrointestinal neurodevelopmental syndrome, OMIM:619318
Intellectual disability v3.1118 ANKRD17 Arina Puzriakova Classified gene: ANKRD17 as Amber List (moderate evidence)
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 v3.1118 ANKRD17 Arina Puzriakova Gene: ankrd17 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1117 ANKRD17 Arina Puzriakova Tag Q2_21_rating tag was added to gene: ANKRD17.
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: SMARCA5.
Tag Q2_21_NHS_review tag was added to gene: SMARCA5.
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Classified gene: SMARCA5 as Amber List (moderate evidence)
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 v3.1117 SMARCA5 Arina Puzriakova Gene: smarca5 has been classified as Amber List (Moderate Evidence).
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 v3.1115 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive 270800 to Spastic paraplegia 5A, autosomal recessive , OMIM:270800
Intellectual disability v3.1114 CYP7B1 Arina Puzriakova Mode of inheritance for gene: CYP7B1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1113 CYP7B1 Arina Puzriakova Classified gene: CYP7B1 as Red List (low evidence)
Intellectual disability v3.1113 CYP7B1 Arina Puzriakova Gene: cyp7b1 has been classified as Red List (Low Evidence).
Intellectual disability v3.1112 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
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 v3.1110 POGZ Arina Puzriakova Phenotypes for gene: POGZ were changed from INTELLECTUAL DISABILITY to White-Sutton syndrome, OMIM:616364
Intellectual disability v3.1109 POGZ Arina Puzriakova Publications for gene: POGZ were set to 25533962
Intellectual disability v3.1108 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to
Intellectual disability v3.1107 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant, 613454; CONGENITAL VARIANT OF RETT SYNDROME (RTTCV) to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Intellectual disability v3.1106 SMARCE1 Arina Puzriakova Phenotypes for gene: SMARCE1 were changed from COFFIN SIRIS to Coffin-Siris syndrome 5, OMIM:616938
Intellectual disability v3.1105 SMARCC1 Arina Puzriakova Mode of inheritance for gene: SMARCC1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1104 DPH1 Arina Puzriakova Publications for gene: DPH1 were set to 29362492; 29410513; 26220823; 25558065
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 v3.1102 SLC6A1 Arina Puzriakova Publications for gene: SLC6A1 were set to 25865495
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 v3.1100 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from ?Ribose 5-phosphate isomerase deficiency, 608611; Ribose 5-phosphate isomerase deficiency, MIM 608611. to Ribose 5-phosphate isomerase deficiency, OMIM:608611
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 v3.1098 SCYL1 Sarah Leigh Tag watchlist was removed from gene: SCYL1.
Tag Q2_21_rating tag was added to gene: SCYL1.
Intellectual disability v3.1098 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711
Intellectual disability v3.1097 SCYL1 Sarah Leigh reviewed gene: SCYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1097 SCYL1 Sarah Leigh Publications for gene: SCYL1 were set to 26581903; 30914295
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 v3.1095 PRICKLE1 Sarah Leigh Phenotypes for gene: PRICKLE1 were changed from Epilepsy, progressive myoclonic 1B, 612437 to Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904
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 Tag Q2_21_rating tag was added to gene: UFSP2.
Intellectual disability v3.1094 UFSP2 Sarah Leigh Classified gene: UFSP2 as Amber List (moderate evidence)
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 v3.1094 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
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 v3.1093 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus to Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Intellectual disability v3.1092 UFSP2 Sarah Leigh Tag founder-effect tag was added to gene: UFSP2.
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 v3.1092 CAMK2B Arina Puzriakova Publications for gene: CAMK2B were set to
Intellectual disability v3.1091 CAMK2B Arina Puzriakova Phenotypes for gene: CAMK2B were changed from Mental retardation, autosomal dominant 54 617799 to Mental retardation, autosomal dominant 54, OMIM:617799
Intellectual disability v3.1090 YIPF5 Arina Puzriakova Entity copied from Severe microcephaly v2.170
Intellectual disability v3.1090 YIPF5 Arina Puzriakova gene: YIPF5 was added
gene: YIPF5 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: YIPF5.
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Intellectual disability v3.1089 UNC80 Arina Puzriakova Publications for gene: UNC80 were set to 25529582; 2670875126708753
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 v3.1086 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 0
Intellectual disability v3.1085 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Intellectual disability v3.1084 AFG3L2 Sarah Leigh commented on gene: AFG3L2: Disease causing variants are both monoallelic and biallelic
Intellectual disability v3.1084 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive, 614487 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Intellectual disability v3.1083 AFG3L2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: AFG3L2.
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 v3.1083 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from delayed developmental milestones; Pontocerebellar hypoplasia, type 2F, 617026; Intellectual disability to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Intellectual disability v3.1082 TRIO Arina Puzriakova Publications for gene: TRIO were set to 0
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 v3.1080 TRAPPC9 Arina Puzriakova Publications for gene: TRAPPC9 were set to
Intellectual disability v3.1079 TRAPPC9 Arina Puzriakova Phenotypes for gene: TRAPPC9 were changed from Mental retardation, autosomal recessive 13, 613192; Mental Retardation, Recessive; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 13 (MRT13) to Mental retardation, autosomal recessive 13, OMIM:613192
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 v3.1077 TRAPPC6B Arina Puzriakova Publications for gene: TRAPPC6B were set to 28626029; 28397838
Intellectual disability v3.1076 MINPP1 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.174
Intellectual disability v3.1076 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Intellectual disability v3.1075 NSF Sarah Leigh reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1075 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
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 Tag Q2_21_rating tag was added to gene: TMEM222.
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 Classified gene: TMEM222 as Amber List (moderate evidence)
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 v3.1072 TMEM222 Sarah Leigh Gene: tmem222 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1071 TMEM222 Sarah Leigh Publications for gene: TMEM222 were set to 33824500
Intellectual disability v3.1070 FARSA Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.79
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 ANKRD17 Zornitza Stark gene: ANKRD17 was added
gene: ANKRD17 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ANKRD17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD17 were set to 33909992
Phenotypes for gene: ANKRD17 were set to Intellectual disability, speech delay, and dysmorphism
Review for gene: ANKRD17 was set to GREEN
gene: ANKRD17 was marked as current diagnostic
Added comment: 34 predominantly LoF variants reported - 29 de novo, 1 inherited from an affected parent, 1 inherited from a suspected mosaic parent. Main phenotypes were dev delay/ID, motor delay, and speech delay.
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 v3.1069 CLTC Arina Puzriakova Phenotypes for gene: CLTC were changed from Mental retardation, autosomal dominant 56, 617854; Autosomal dominant non-syndromic intellectual disability, Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854
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 v3.1067 UBTF Arina Puzriakova Publications for gene: UBTF were set to 26350204; 28777933
Intellectual disability v3.1066 VPS11 Ivone Leong commented on gene: VPS11
Intellectual disability v3.1066 VPS11 Ivone Leong Tag watchlist was removed from gene: VPS11.
Tag Q2_21_rating tag was added to gene: VPS11.
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 v3.1064 DNA2 Arina Puzriakova Publications for gene: DNA2 were set to 23352259; 24389050
Intellectual disability v3.1063 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from PRIMORDIAL DWARFISM SECKEL SYNDROME 8; SCKL8 to Seckel syndrome 8, OMIM:615807
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 v3.1061 WDR4 Ivone Leong Tag Q2_21_rating tag was added to gene: WDR4.
Intellectual disability v3.1061 WDR4 Ivone Leong Publications for gene: WDR4 were set to 29597095; 26416026
Intellectual disability v3.1060 OCRL Eleanor Williams Publications for gene: OCRL were set to
Intellectual disability v3.1059 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1059 CDH11 Arina Puzriakova Phenotypes for gene: CDH11 were changed from Elsahy-Waters syndrome to Elsahy-Waters syndrome, OMIM:211380; Teebi hypertelorism syndrome
Intellectual disability v3.1058 CDH11 Arina Puzriakova Publications for gene: CDH11 were set to 27431290; 29271567
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 v3.1057 CDH11 Arina Puzriakova Mode of inheritance for gene: CDH11 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
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 v3.1056 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to 25439727
Intellectual disability v3.1055 FAR1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: FAR1.
Tag Q2_21_MOI tag was added to gene: FAR1.
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 v3.1055 HERC2 Arina Puzriakova Publications for gene: HERC2 were set to 23065719
Intellectual disability v3.1054 HERC2 Arina Puzriakova Phenotypes for gene: HERC2 were changed from Mental retardation, autosomal recessive 38 to Mental retardation, autosomal recessive 38, OMIM:615516
Intellectual disability v3.1053 NUBPL Arina Puzriakova Phenotypes for gene: NUBPL were changed from MITOCHONDRIAL COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 21, OMIM:618242
Intellectual disability v3.1052 INPP4A Arina Puzriakova Phenotypes for gene: INPP4A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual disability; Seizures
Intellectual disability v3.1051 INPP4A Arina Puzriakova Publications for gene: INPP4A were set to 21937992
Intellectual disability v3.1050 INPP4A Arina Puzriakova Classified gene: INPP4A as Amber List (moderate evidence)
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 v3.1050 INPP4A Arina Puzriakova Gene: inpp4a has been classified as Amber List (Moderate Evidence).
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 Tag Q2_21_rating tag was added to gene: UBE4A.
Intellectual disability v3.1049 UBE4A Arina Puzriakova Classified gene: UBE4A as Amber List (moderate evidence)
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 v3.1049 UBE4A Arina Puzriakova Gene: ube4a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1048 NCDN Arina Puzriakova Tag Q2_21_rating tag was added to gene: NCDN.
Intellectual disability v3.1048 NCDN Arina Puzriakova Classified gene: NCDN as Amber List (moderate evidence)
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 v3.1048 NCDN Arina Puzriakova Gene: ncdn has been classified as Amber List (Moderate Evidence).
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 v3.1046 MAPKAPK5 Arina Puzriakova Tag watchlist tag was added to gene: MAPKAPK5.
Intellectual disability v3.1046 MAPKAPK5 Arina Puzriakova Publications for gene: MAPKAPK5 were set to 3344202
Intellectual disability v3.1045 MAPKAPK5 Arina Puzriakova Classified gene: MAPKAPK5 as Amber List (moderate evidence)
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 v3.1045 MAPKAPK5 Arina Puzriakova Gene: mapkapk5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1044 COPB1 Arina Puzriakova Tag watchlist tag was added to gene: COPB1.
Intellectual disability v3.1044 COPB1 Arina Puzriakova Classified gene: COPB1 as Amber List (moderate evidence)
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 v3.1044 COPB1 Arina Puzriakova Gene: copb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1043 COPB1 Arina Puzriakova Phenotypes for gene: COPB1 were changed from Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts to Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly
Intellectual disability v3.1042 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome 617159 to Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Intellectual disability v3.1041 PIGC Arina Puzriakova Classified gene: PIGC as Amber List (moderate evidence)
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 v3.1041 PIGC Arina Puzriakova Gene: pigc has been classified as Amber List (Moderate Evidence).
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 v3.1039 PIGC Arina Puzriakova Publications for gene: PIGC were set to 27694521
Intellectual disability v3.1038 PIGC Arina Puzriakova Tag Q2_21_rating tag was added to gene: PIGC.
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 v3.1038 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15, 614947 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
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 v3.1036 LAMA1 Sarah Leigh Publications for gene: LAMA1 were set to 21937992; 30244536
Intellectual disability v3.1035 NEUROD2 Arina Puzriakova Classified gene: NEUROD2 as Amber List (moderate evidence)
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 v3.1035 NEUROD2 Arina Puzriakova Gene: neurod2 has been classified as Amber List (Moderate Evidence).
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 Tag Q2_21_rating tag was added to gene: NCKAP1.
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Classified gene: NCKAP1 as Amber List (moderate evidence)
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 v3.1033 NCKAP1 Arina Puzriakova Gene: nckap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1032 NCKAP1 Arina Puzriakova Phenotypes for gene: NCKAP1 were changed from to Intellectual disability; Autism
Intellectual disability v3.1031 NCKAP1 Arina Puzriakova Publications for gene: NCKAP1 were set to
Intellectual disability v3.1030 NCKAP1 Arina Puzriakova Mode of inheritance for gene: NCKAP1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1029 DPYS Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: DPYS.
Intellectual disability v3.1029 DPYS Arina Puzriakova Publications for gene: DPYS were set to
Intellectual disability v3.1028 DPYS Arina Puzriakova Classified gene: DPYS as Amber List (moderate evidence)
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 v3.1028 DPYS Arina Puzriakova Gene: dpys has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1027 DPYS Arina Puzriakova Phenotypes for gene: DPYS were changed from Dihydropyrimidinuria, MIM#222748 to Dihydropyrimidinuria, OMIM:222748
Intellectual disability v3.1026 DPM2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DPM2.
Intellectual disability v3.1026 DPM2 Arina Puzriakova Publications for gene: DPM2 were set to 23109149
Intellectual disability v3.1025 DPM2 Arina Puzriakova Classified gene: DPM2 as Amber List (moderate evidence)
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 v3.1025 DPM2 Arina Puzriakova Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1024 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu to Congenital disorder of glycosylation, type Iu, OMIM:615042
Intellectual disability v3.1023 B4GALT1 Arina Puzriakova Publications for gene: B4GALT1 were set to 26503795; 24896178; 11901181; 21920538; 30653653
Intellectual disability v3.1022 B4GALT1 Arina Puzriakova Classified gene: B4GALT1 as Amber List (moderate evidence)
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 v3.1022 B4GALT1 Arina Puzriakova Gene: b4galt1 has been classified as Amber List (Moderate Evidence).
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 v3.1021 B4GALT1 Arina Puzriakova Publications for gene: B4GALT1 were set to 26503795; 24896178; 11901181; 21920538
Intellectual disability v3.1020 B4GALT1 Arina Puzriakova Phenotypes for gene: B4GALT1 were changed from Congenital disorder of glycosylation, type IId 607091 to Congenital disorder of glycosylation, type IId, OMIM:607091
Intellectual disability v3.1019 AGO1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: AGO1.
Intellectual disability v3.1019 AGO1 Arina Puzriakova commented on gene: AGO1
Intellectual disability v3.1019 AGO1 Arina Puzriakova Publications for gene: AGO1 were set to 26350204; 30213762; 22495306; 23020937; 25363768; 25356899; 27620904; 29346770
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 v3.1016 KCNH1 Arina Puzriakova Publications for gene: KCNH1 were set to 25420144; 33594261
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 COPB1 Zornitza Stark gene: COPB1 was added
gene: COPB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts
Review for gene: COPB1 was set to AMBER
Added comment: Two unrelated families, some supportive functional data.
Sources: Literature
Intellectual disability 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 v3.1013 EBF3 Sarah Leigh Phenotypes for gene: EBF3 were changed from Hypotonia, ataxia, and delayed development syndrome 617330 to Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021
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 v3.1011 KCNQ2 Arina Puzriakova Publications for gene: KCNQ2 were set to
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 v3.1009 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to 0
Intellectual disability v3.1008 FAR1 Arina Puzriakova Phenotypes for gene: FAR1 were changed from SEVERE INTELLECTUAL DISABILITY, EPILEPSY, AND CATARACTS to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Intellectual disability v3.1007 LARS2 Arina Puzriakova Publications for gene: LARS2 were set to
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 Classified gene: LARS2 as Amber List (moderate evidence)
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 v3.1006 LARS2 Arina Puzriakova Gene: lars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1005 LARS2 Arina Puzriakova Phenotypes for gene: LARS2 were changed from to Perrault syndrome 4, OMIM:615300; Hydrops, lactic acidosis, and sideroblastic anemia, OMIM:617021; Leukodystrophy
Intellectual disability v3.1004 LARS2 Arina Puzriakova Mode of inheritance for gene: LARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
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 DPYS Zornitza Stark gene: DPYS was added
gene: DPYS was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: DPYS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DPYS were set to Dihydropyrimidinuria, MIM#222748
Review for gene: DPYS was set to GREEN
gene: DPYS was marked as current diagnostic
Added comment: Highly variable phenotype, but many have ID.
Sources: Expert Review
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 v3.1003 CLN5 Sarah Leigh Phenotypes for gene: CLN5 were changed from Ceroid lipofuscinosis, neuronal, 5, 256731; NEURONAL CEROID LIPOFUSCINOSIS TYPE 5 (CLN5) to Ceroid lipofuscinosis, neuronal, 5 OMIM:256731; neuronal ceroid lipofuscinosis 5 MONDO:0009745
Intellectual disability v3.1002 BBS1 Sarah Leigh Publications for gene: BBS1 were set to
Intellectual disability v3.1001 BBS1 Sarah Leigh Phenotypes for gene: BBS1 were changed from Bardet-Biedl syndrome 1, 209900; BARDET-BIEDL SYNDROME TYPE 1 (BBS1) to Bardet-Biedl syndrome 1 OMIM:209900; Bardet-Biedl syndrome 1 MONDO:0008854
Intellectual disability v3.1000 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 27679995; 30012219; 29531481; 29531481; 31612321
Intellectual disability v3.999 ATP8A2 Sarah Leigh Publications for gene: ATP8A2 were set to 22892528; 27679995; 30012219; 29531481
Intellectual disability v3.998 ATP8A2 Sarah Leigh Phenotypes for gene: ATP8A2 were changed from ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 615268; intellectual disability to ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 OMIM:615268; cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 MONDO:0014104
Intellectual disability v3.997 SPEN Arina Puzriakova Publications for gene: SPEN were set to 33057194
Intellectual disability v3.996 SPEN Arina Puzriakova Classified gene: SPEN as Amber List (moderate evidence)
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 v3.996 SPEN Arina Puzriakova Gene: spen has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.995 SPEN Arina Puzriakova Tag Q2_21_rating tag was added to gene: SPEN.
Intellectual disability v3.995 MED27 Arina Puzriakova Phenotypes for gene: MED27 were changed from Intellectual disability; cerebellar hypoplasia; dystonia to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy
Intellectual disability v3.994 MED27 Arina Puzriakova Classified gene: MED27 as Amber List (moderate evidence)
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 v3.994 MED27 Arina Puzriakova Gene: med27 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.993 MED27 Arina Puzriakova Tag Q2_21_rating tag was added to gene: MED27.
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 Tag Q2_21_rating tag was added to gene: EIF5A.
Intellectual disability v3.993 EIF5A Arina Puzriakova Classified gene: EIF5A as Amber List (moderate evidence)
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 v3.993 EIF5A Arina Puzriakova Gene: eif5a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.992 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder, 613078 to Nijmegen breakage syndrome-like disorder, OMIM:613078
Intellectual disability v3.991 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 1887849; 19409520; 32212377
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 v3.990 ALDH5A1 Sarah Leigh Publications for gene: ALDH5A1 were set to
Intellectual disability v3.989 ALDH5A1 Sarah Leigh Phenotypes for gene: ALDH5A1 were changed from Succinic semialdehyde dehydrogenase deficiency, 271980; SUCCINATE SEMIALDEHYDE DEHYDROGENASE DEFICIENCY to Succinic semialdehyde dehydrogenase deficiency OMIM:271980; succinic semialdehyde dehydrogenase deficiency MONDO:0010083
Intellectual disability v3.988 GNB1 Arina Puzriakova Phenotypes for gene: GNB1 were changed from Intellectual disability; developmental delay; Global developmental delay to Mental retardation, autosomal dominant 42, OMIM:616973
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 v3.986 ADPRHL2 Sarah Leigh Publications for gene: ADPRHL2 were set to 30100084
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 v3.985 TMPRSS9 Arina Puzriakova Mode of inheritance for gene: TMPRSS9 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
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 Classified gene: DDB1 as Amber List (moderate evidence)
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 v3.983 DDB1 Arina Puzriakova Gene: ddb1 has been classified as Amber List (Moderate Evidence).
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 Tag Q2_21_rating tag was added to gene: DDB1.
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 GSPT2 Arina Puzriakova Tag watchlist tag was added to gene: GSPT2.
Intellectual disability v3.981 GSPT2 Arina Puzriakova commented on gene: GSPT2
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 v3.980 SMARCB1 Arina Puzriakova Phenotypes for gene: SMARCB1 were changed from Rhabdoid tumors, somatic, 609322Rhabdoid predisposition syndrome 1, 609322Mental retardation, autosomal dominant 15, 614608; RHABDOID PREDISPOSITION SYNDROME 1 to Coffin-Siris syndrome 3, OMIM:614608
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 v3.979 SMARCA4 Arina Puzriakova Phenotypes for gene: SMARCA4 were changed from Rhabdoid tumor predisposition syndrome 2, 613325Mental retardation, autosomal dominant 16, 614609; COFFIN SIRIS to Coffin-Siris syndrome 4, OMIM:614609
Intellectual disability v3.978 POLD1 Arina Puzriakova Phenotypes for gene: POLD1 were changed from {Colorectal cancer, susceptibility to, 10}, 612591; Mandibular; hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, 615381 to {Colorectal cancer, susceptibility to, 10}, 612591; Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, 615381
Intellectual disability v3.977 SIAH1 Arina Puzriakova Classified gene: SIAH1 as Amber List (moderate evidence)
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 v3.977 SIAH1 Arina Puzriakova Gene: siah1 has been classified as Amber List (Moderate Evidence).
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 MED27 Zornitza Stark gene: MED27 was added
gene: MED27 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED27 were set to 33443317
Phenotypes for gene: MED27 were set to Intellectual disability; cerebellar hypoplasia; dystonia
Review for gene: MED27 was set to GREEN
gene: MED27 was marked as current diagnostic
Added comment: 16 patients from 11 families reported
Sources: Literature
Intellectual disability 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 v3.975 ERBB4 Sarah Leigh Publications for gene: ERBB4 were set to 33603162; 23633123; 15219717; 30498032
Intellectual disability v3.974 ERBB4 Sarah Leigh Tag Q2_21_rating tag was added to gene: ERBB4.
Intellectual disability v3.974 ERBB4 Sarah Leigh Publications for gene: ERBB4 were set to 33603162; 23633123
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 Classified gene: ERBB4 as Amber List (moderate evidence)
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 v3.973 ERBB4 Sarah Leigh Gene: erbb4 has been classified as Amber List (Moderate Evidence).
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 v3.972 ERBB4 Sarah Leigh Phenotypes for gene: ERBB4 were changed from intellectual disability; epilepsy to intellectual disability MONDO:0001071
Intellectual disability v3.971 ERBB4 Sarah Leigh Publications for gene: ERBB4 were set to 33603162; 23633123
Intellectual disability v3.971 ERBB4 Sarah Leigh Publications for gene: ERBB4 were set to 33603162
Intellectual disability v3.970 SETD1B Arina Puzriakova Publications for gene: SETD1B were set to 29322246; 27106595; 25428890; 31110234
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 v3.968 ACO2 Arina Puzriakova Phenotypes for gene: ACO2 were changed from INFANTILE CEREBELLAR-RETINAL DEGENERATION to Infantile cerebellar-retinal degeneration, OMIM:614559; Infantile cerebellar-retinal degeneration, MONDO:0013802
Intellectual disability v3.967 KCNN3 Arina Puzriakova Publications for gene: KCNN3 were set to 31155282
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 PPP2R2B_CAG Arina Puzriakova Tag curated_removed tag was added to STR: PPP2R2B_CAG.
Intellectual disability v3.966 CSTB_CCCCGCCCCGCG Arina Puzriakova Tag curated_removed tag was added to STR: CSTB_CCCCGCCCCGCG.
Intellectual disability v3.966 C9orf72_GGGGCC Arina Puzriakova Tag curated_removed tag was added to STR: C9orf72_GGGGCC.
Intellectual disability v3.966 ATXN7_CAG Arina Puzriakova Tag curated_removed tag was added to STR: ATXN7_CAG.
Intellectual disability v3.966 ATXN3_CAG Arina Puzriakova Tag curated_removed tag was added to STR: ATXN3_CAG.
Intellectual disability v3.966 ATXN1_CAG Arina Puzriakova Tag curated_removed tag was added to STR: ATXN1_CAG.
Intellectual disability v3.966 FXN_GAA Arina Puzriakova Tag curated_removed tag was added to STR: FXN_GAA.
Intellectual disability v3.966 ATXN10_ATTCT Arina Puzriakova Tag curated_removed tag was added to STR: ATXN10_ATTCT.
Intellectual disability v3.966 ATXN2_CAG Arina Puzriakova Tag curated_removed tag was added to STR: ATXN2_CAG.
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 v3.966 KCNN3 Arina Puzriakova Phenotypes for gene: KCNN3 were changed from Zimmermann-Laband syndrome 3; OMIM# 618658 to Zimmermann-Laband syndrome 3, OMIM:618658
Intellectual disability v3.965 KCNH1 Arina Puzriakova Publications for gene: KCNH1 were set to 25420144
Intellectual disability v3.964 KCNH1 Arina Puzriakova Phenotypes for gene: KCNH1 were changed from TEMPLE BARRAISTER SYNDROME to Temple-Baraitser syndrome, OMIM:611816; Temple-Baraitser syndrome, MONDO:0012735; Zimmermann-Laband syndrome 1, OMIM:135500; Zimmermann-Laband syndrome 1, MONDO:0024526
Intellectual disability v3.963 ERBB4 Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: ERBB4.
Intellectual disability v3.963 CXorf56 Catherine Snow Tag new-gene-name tag was added to gene: CXorf56.
Intellectual disability v3.963 CXorf56 Catherine Snow commented on gene: CXorf56
Intellectual disability v3.963 MPP5 Catherine Snow Tag new-gene-name tag was added to gene: MPP5.
Intellectual disability v3.963 MPP5 Catherine Snow commented on gene: MPP5
Intellectual disability v3.963 ARMC4 Catherine Snow Tag new-gene-name tag was added to gene: ARMC4.
Intellectual disability v3.963 ARMC4 Catherine Snow commented on gene: ARMC4
Intellectual disability v3.963 CCDC114 Catherine Snow Tag new-gene-name tag was added to gene: CCDC114.
Intellectual disability v3.963 CCDC114 Catherine Snow commented on gene: CCDC114
Intellectual disability v3.963 C12orf65 Catherine Snow Tag new-gene-name tag was added to gene: C12orf65.
Intellectual disability v3.963 C12orf65 Catherine Snow commented on gene: C12orf65
Intellectual disability v3.963 FAM160B1 Catherine Snow Tag new-gene-name tag was added to gene: FAM160B1.
Intellectual disability v3.963 FAM160B1 Catherine Snow commented on gene: FAM160B1
Intellectual disability v3.963 LRRC6 Catherine Snow Tag new-gene-name tag was added to gene: LRRC6.
Intellectual disability v3.963 LRRC6 Catherine Snow commented on gene: LRRC6
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 v3.963 CLP1 Sarah Leigh Phenotypes for gene: CLP1 were changed from PONTOCEREBELLAR HYPOPLASIA, TYPE 10 to Pontocerebellar hypoplasia 10 OMIM:615803; Pontocerebellar hypoplasia type 10 MONDO:0014349
Intellectual disability v3.962 CLP1 Sarah Leigh Tag founder-effect tag was added to gene: CLP1.
Intellectual disability v3.962 ATCAY Catherine Snow Source: Expert Review Amber was removed from gene: ATCAY
Intellectual disability v3.961 ANO3 Catherine Snow Source: Expert Review Amber was removed from gene: ANO3
Intellectual disability v3.960 ADGRV1 Catherine Snow Source: Expert Review Amber was removed from gene: ADGRV1
Intellectual disability v3.959 ABHD12 Catherine Snow Source: Expert Review Amber was removed from gene: ABHD12
Intellectual disability v3.958 CDK16 Catherine Snow Source: Expert Review Red was removed from gene: CDK16
Intellectual disability v3.957 ZC3H14 Catherine Snow Source: Expert Review Red was removed from gene: ZC3H14
Intellectual disability v3.956 XPA Catherine Snow Source: Expert Review Red was removed from gene: XPA
Intellectual disability v3.955 USP27X Catherine Snow Source: Expert Review Red was removed from gene: USP27X
Intellectual disability v3.953 TUBGCP4 Catherine Snow Source: Expert Review Red was removed from gene: TUBGCP4
Intellectual disability v3.952 TRAPPC11 Catherine Snow Source: Expert Review Red was removed from gene: TRAPPC11
Intellectual disability v3.951 TMEM231 Catherine Snow Source: Expert Review Red was removed from gene: TMEM231
Intellectual disability v3.950 SRGAP3 Catherine Snow Source: Expert Review Red was removed from gene: SRGAP3
Intellectual disability v3.949 SMARCD2 Catherine Snow Source: Expert Review Red was removed from gene: SMARCD2
Intellectual disability v3.947 SACS Catherine Snow Source: Expert Review Red was removed from gene: SACS
Intellectual disability v3.946 RAX Catherine Snow Source: Expert Review Red was removed from gene: RAX
Intellectual disability v3.945 WT1 Arina Puzriakova Source: Expert Review Amber was removed from gene: WT1
Intellectual disability v3.944 NUP62 Catherine Snow Source: Expert Review Red was removed from gene: NUP62
Intellectual disability v3.943 NDUFAF2 Catherine Snow Source: Expert Review Red was removed from gene: NDUFAF2
Intellectual disability v3.942 MIR17HG Catherine Snow Source: Expert Review Red was removed from gene: MIR17HG
Intellectual disability v3.941 VPS35 Arina Puzriakova Source: Expert Review Amber was removed from gene: VPS35
Intellectual disability v3.940 TTPA Arina Puzriakova Source: Expert Review Amber was removed from gene: TTPA
Intellectual disability v3.939 MAPK10 Catherine Snow Source: Expert Review Red was removed from gene: MAPK10
Intellectual disability v3.938 TTC7A Arina Puzriakova Source: Expert Review Amber was removed from gene: TTC7A
Intellectual disability v3.937 TTBK2 Arina Puzriakova Source: Expert Review Amber was removed from gene: TTBK2
Intellectual disability v3.936 KLHL15 Catherine Snow Source: Expert Review Red was removed from gene: KLHL15
Intellectual disability v3.935 HAX1 Catherine Snow Source: Expert Review Red was removed from gene: HAX1
Intellectual disability v3.934 TGM6 Arina Puzriakova Source: Expert Review Amber was removed from gene: TGM6
Intellectual disability v3.933 TFG Arina Puzriakova Source: Expert Review Amber was removed from gene: TFG
Intellectual disability v3.932 TFAP2B Arina Puzriakova Source: Expert Review Amber was removed from gene: TFAP2B
Intellectual disability v3.931 TFAP2A Arina Puzriakova Source: Expert Review Amber was removed from gene: TFAP2A
Intellectual disability v3.930 TBP Arina Puzriakova Source: Expert Review Amber was removed from gene: TBP
Intellectual disability v3.929 TARDBP Arina Puzriakova Source: Expert Review Amber was removed from gene: TARDBP
Intellectual disability v3.928 STUB1 Arina Puzriakova Source: Expert Review Amber was removed from gene: STUB1
Intellectual disability v3.927 PLEC Sarah Leigh Source: Expert Review Amber was removed from gene: PLEC
Intellectual disability v3.926 SPG7 Arina Puzriakova Source: Expert Review Amber was removed from gene: SPG7
Intellectual disability v3.926 PLCE1 Sarah Leigh Source: Expert Review Amber was removed from gene: PLCE1
Intellectual disability v3.925 SPG21 Arina Puzriakova Source: Expert Review Amber was removed from gene: SPG21
Intellectual disability v3.924 PINK1 Sarah Leigh Source: Expert Review Amber was removed from gene: PINK1
Intellectual disability v3.923 SNCA Arina Puzriakova Source: Expert Review Amber was removed from gene: SNCA
Intellectual disability v3.922 PDYN Sarah Leigh Source: Expert Review Amber was removed from gene: PDYN
Intellectual disability v3.922 SMO Arina Puzriakova Source: Expert Review Amber was removed from gene: SMO
Intellectual disability v3.922 PDGFB Sarah Leigh Source: Expert Review Amber was removed from gene: PDGFB
Intellectual disability v3.921 PCYT1A Sarah Leigh Source: Expert Review Amber was removed from gene: PCYT1A
Intellectual disability v3.921 SLC20A2 Arina Puzriakova Source: Expert Review Amber was removed from gene: SLC20A2
Intellectual disability v3.920 PARK7 Sarah Leigh Source: Expert Review Amber was removed from gene: PARK7
Intellectual disability v3.919 SIGMAR1 Arina Puzriakova Source: Expert Review Amber was removed from gene: SIGMAR1
Intellectual disability v3.919 PALB2 Sarah Leigh Source: Expert Review Amber was removed from gene: PALB2
Intellectual disability v3.918 NPHS2 Sarah Leigh Source: Expert Review Amber was removed from gene: NPHS2
Intellectual disability v3.917 NOP56 Sarah Leigh Source: Expert Review Amber was removed from gene: NOP56
Intellectual disability v3.916 SH3TC2 Arina Puzriakova Source: Expert Review Amber was removed from gene: SH3TC2
Intellectual disability v3.915 SGCE Arina Puzriakova Source: Expert Review Amber was removed from gene: SGCE
Intellectual disability v3.914 NIPA1 Sarah Leigh Source: Expert Review Amber was removed from gene: NIPA1
Intellectual disability v3.913 SETX Arina Puzriakova Source: Expert Review Amber was removed from gene: SETX
Intellectual disability v3.912 NHLRC1 Sarah Leigh Source: Expert Review Amber was removed from gene: NHLRC1
Intellectual disability v3.911 SCN9A Arina Puzriakova Source: Expert Review Amber was removed from gene: SCN9A
Intellectual disability v3.911 NHEJ1 Sarah Leigh Source: Expert Review Amber was removed from gene: NHEJ1
Intellectual disability v3.910 SCARB2 Arina Puzriakova Source: Expert Review Amber was removed from gene: SCARB2
Intellectual disability v3.909 NEFL Sarah Leigh Source: Expert Review Amber was removed from gene: NEFL
Intellectual disability v3.908 SBF2 Arina Puzriakova Source: Expert Review Amber was removed from gene: SBF2
Intellectual disability v3.908 NDRG1 Sarah Leigh Source: Expert Review Amber was removed from gene: NDRG1
Intellectual disability v3.907 MTPAP Sarah Leigh Source: Expert Review Amber was removed from gene: MTPAP
Intellectual disability v3.906 RTN2 Arina Puzriakova Source: Expert Review Amber was removed from gene: RTN2
Intellectual disability v3.906 MTMR2 Sarah Leigh Source: Expert Review Amber was removed from gene: MTMR2
Intellectual disability v3.905 RNF216 Arina Puzriakova Source: Expert Review Amber was removed from gene: RNF216
Intellectual disability v3.904 RIPK4 Arina Puzriakova Source: Expert Review Amber was removed from gene: RIPK4
Intellectual disability v3.903 RFX6 Arina Puzriakova Source: Expert Review Amber was removed from gene: RFX6
Intellectual disability v3.902 REEP2 Arina Puzriakova Source: Expert Review Amber was removed from gene: REEP2
Intellectual disability v3.901 REEP1 Arina Puzriakova Source: Expert Review Amber was removed from gene: REEP1
Intellectual disability v3.900 MPZ Sarah Leigh Source: Expert Review Amber was removed from gene: MPZ
Intellectual disability v3.899 PSEN1 Arina Puzriakova Source: Expert Review Amber was removed from gene: PSEN1
Intellectual disability v3.899 MMP21 Sarah Leigh Source: Expert Review Amber was removed from gene: MMP21
Intellectual disability v3.898 MITF Sarah Leigh Source: Expert Review Amber was removed from gene: MITF
Intellectual disability v3.897 PRX Arina Puzriakova Source: Expert Review Amber was removed from gene: PRX
Intellectual disability v3.896 MECR Sarah Leigh Source: Expert Review Amber was removed from gene: MECR
Intellectual disability v3.895 MARS2 Sarah Leigh Source: Expert Review Amber was removed from gene: MARS2
Intellectual disability v3.894 PRKRA Arina Puzriakova Source: Expert Review Amber was removed from gene: PRKRA
Intellectual disability v3.894 MAFB Sarah Leigh Source: Expert Review Amber was removed from gene: MAFB
Intellectual disability v3.893 LRRK2 Sarah Leigh Source: Expert Review Amber was removed from gene: LRRK2
Intellectual disability v3.893 PRKN Arina Puzriakova Source: Expert Review Amber was removed from gene: PRKN
Intellectual disability v3.893 LOXHD1 Sarah Leigh Source: Expert Review Amber was removed from gene: LOXHD1
Intellectual disability v3.892 PRKCG Arina Puzriakova Source: Expert Review Amber was removed from gene: PRKCG
Intellectual disability v3.892 LITAF Sarah Leigh Source: Expert Review Amber was removed from gene: LITAF
Intellectual disability v3.891 PRICKLE2 Arina Puzriakova Source: Expert Review Amber was removed from gene: PRICKLE2
Intellectual disability v3.891 KIF1C Sarah Leigh Source: Expert Review Amber was removed from gene: KIF1C
Intellectual disability v3.890 KCNE1 Sarah Leigh Source: Expert Review Amber was removed from gene: KCNE1
Intellectual disability v3.889 PRICKLE1 Arina Puzriakova Source: Expert Review Amber was removed from gene: PRICKLE1
Intellectual disability v3.889 KCNA1 Sarah Leigh Source: Expert Review Amber was removed from gene: KCNA1
Intellectual disability v3.888 ITGA3 Sarah Leigh Source: Expert Review Amber was removed from gene: ITGA3
Intellectual disability v3.887 PPP2R2B Arina Puzriakova Source: Expert Review Amber was removed from gene: PPP2R2B
Intellectual disability v3.886 IGHMBP2 Sarah Leigh Source: Expert Review Amber was removed from gene: IGHMBP2
Intellectual disability v3.885 PNKD Arina Puzriakova Source: Expert Review Amber was removed from gene: PNKD
Intellectual disability v3.884 DCTN1 Sarah Leigh Source: Expert Review Amber was removed from gene: DCTN1
Intellectual disability v3.883 DHODH Sarah Leigh Source: Expert Review Amber was removed from gene: DHODH
Intellectual disability v3.882 DNM2 Sarah Leigh Source: Expert Review Amber was removed from gene: DNM2
Intellectual disability v3.881 EFHC1 Sarah Leigh Source: Expert Review Amber was removed from gene: EFHC1
Intellectual disability v3.880 EIF4G1 Sarah Leigh Source: Expert Review Amber was removed from gene: EIF4G1
Intellectual disability v3.879 ELOVL5 Sarah Leigh Source: Expert Review Amber was removed from gene: ELOVL5
Intellectual disability v3.878 EPM2A Sarah Leigh Source: Expert Review Amber was removed from gene: EPM2A
Intellectual disability v3.877 FAM111B Sarah Leigh Source: Expert Review Amber was removed from gene: FAM111B
Intellectual disability v3.876 GDAP1 Sarah Leigh Source: Expert Review Amber was removed from gene: GDAP1
Intellectual disability v3.875 GNAL Sarah Leigh Source: Expert Review Amber was removed from gene: GNAL
Intellectual disability v3.874 GORAB Sarah Leigh Source: Expert Review Amber was removed from gene: GORAB
Intellectual disability v3.873 GOSR2 Sarah Leigh Source: Expert Review Amber was removed from gene: GOSR2
Intellectual disability v3.872 GRN Sarah Leigh Source: Expert Review Amber was removed from gene: GRN
Intellectual disability v3.871 MDH2 Ivone Leong Source: Expert Review Amber was removed from gene: MDH2
Intellectual disability v3.870 KNL1 Ivone Leong Source: Expert Review Amber was removed from gene: KNL1
Intellectual disability v3.869 KIAA0586 Ivone Leong Source: Expert Review Amber was removed from gene: KIAA0586
Intellectual disability v3.868 HECW2 Ivone Leong commented on gene: HECW2
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 v3.866 HECW2 Ivone Leong Publications for gene: HECW2 were set to
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 v3.864 IFT140 Sarah Leigh Source: Expert Review Amber was removed from gene: IFT140
Intellectual disability v3.863 FLAD1 Sarah Leigh Source: Expert Review Amber was removed from gene: FLAD1
Intellectual disability v3.862 DNMT1 Sarah Leigh Source: Expert Review Amber was removed from gene: DNMT1
Intellectual disability v3.861 Ivone Leong removed gene:HECW2 from the panel
Intellectual disability v3.860 HACE1 Ivone Leong Source: Expert Review Amber was removed from gene: HACE1
Intellectual disability v3.859 GRID2 Ivone Leong Source: Expert Review Amber was removed from gene: GRID2
Intellectual disability v3.858 GLIS3 Ivone Leong Source: Expert Review Amber was removed from gene: GLIS3
Intellectual disability v3.857 FGF12 Ivone Leong Source: Expert Review Amber was removed from gene: FGF12
Intellectual disability v3.857 GJB1 Catherine Snow Source: Expert Review Red was removed from gene: GJB1
Intellectual disability v3.856 EBF3 Ivone Leong Source: Expert Review Amber was removed from gene: EBF3
Intellectual disability v3.855 CHD4 Ivone Leong Source: Expert Review Amber was removed from gene: CHD4
Intellectual disability v3.854 BRPF1 Ivone Leong Source: Expert Review Amber was removed from gene: BRPF1
Intellectual disability v3.854 GBA2 Catherine Snow Source: Expert Review Red was removed from gene: GBA2
Intellectual disability v3.853 BMP4 Ivone Leong Source: Expert Review Amber was removed from gene: BMP4
Intellectual disability v3.852 ACADS Ivone Leong Source: Expert Review Amber was removed from gene: ACADS
Intellectual disability v3.851 AAAS Ivone Leong Source: Expert Review Amber was removed from gene: AAAS
Intellectual disability v3.851 FRAS1 Catherine Snow Source: Expert Review Red was removed from gene: FRAS1
Intellectual disability v3.850 FAM120C Catherine Snow Source: Expert Review Red was removed from gene: FAM120C
Intellectual disability v3.850 MBTPS2 Ivone Leong Source: Expert Review Red was removed from gene: MBTPS2
Intellectual disability v3.850 CSF1R Sarah Leigh Source: Expert Review Amber was removed from gene: CSF1R
Intellectual disability v3.849 FAAH2 Catherine Snow Source: Expert Review Red was removed from gene: FAAH2
Intellectual disability v3.849 UBTF Ivone Leong Source: Expert Review Red was removed from gene: UBTF
Intellectual disability v3.848 ERMARD Catherine Snow Source: Expert Review Red was removed from gene: ERMARD
Intellectual disability v3.847 THOC2 Ivone Leong Source: Expert Review Red was removed from gene: THOC2
Intellectual disability v3.847 CRYGC Sarah Leigh Source: Expert Review Amber was removed from gene: CRYGC
Intellectual disability v3.846 TECPR2 Ivone Leong Source: Expert Review Red was removed from gene: TECPR2
Intellectual disability v3.845 EPB41L1 Catherine Snow Source: Expert Review Red was removed from gene: EPB41L1
Intellectual disability v3.844 TAF1 Ivone Leong Source: Expert Review Red was removed from gene: TAF1
Intellectual disability v3.843 EEF1B2 Catherine Snow Source: Expert Review Red was removed from gene: EEF1B2
Intellectual disability v3.843 SZT2 Ivone Leong Source: Expert Review Red was removed from gene: SZT2
Intellectual disability v3.842 DPM3 Catherine Snow Source: Expert Review Red was removed from gene: DPM3
Intellectual disability v3.842 ST3GAL5 Ivone Leong Source: Expert Review Red was removed from gene: ST3GAL5
Intellectual disability v3.841 DLG2 Catherine Snow Source: Expert Review Red was removed from gene: DLG2
Intellectual disability v3.840 SMC3 Ivone Leong Source: Expert Review Red was removed from gene: SMC3
Intellectual disability v3.840 DLG1 Catherine Snow Source: Expert Review Red was removed from gene: DLG1
Intellectual disability v3.839 SMAD4 Ivone Leong Source: Expert Review Red was removed from gene: SMAD4
Intellectual disability v3.838 DIP2B Catherine Snow Source: Expert Review Red was removed from gene: DIP2B
Intellectual disability v3.838 SLC33A1 Ivone Leong Source: Expert Review Red was removed from gene: SLC33A1
Intellectual disability v3.837 DDX53 Catherine Snow Source: Expert Review Red was removed from gene: DDX53
Intellectual disability v3.836 SERAC1 Ivone Leong Source: Expert Review Red was removed from gene: SERAC1
Intellectual disability v3.835 RTTN Ivone Leong Source: Expert Review Red was removed from gene: RTTN
Intellectual disability v3.834 CYP7B1 Catherine Snow Source: Expert Review Red was removed from gene: CYP7B1
Intellectual disability v3.834 RLIM Ivone Leong Source: Expert Review Red was removed from gene: RLIM
Intellectual disability v3.833 QARS Ivone Leong Source: Expert Review Red was removed from gene: QARS
Intellectual disability v3.833 CHL1 Catherine Snow Source: Expert Review Red was removed from gene: CHL1
Intellectual disability v3.832 PYCR2 Ivone Leong Source: Expert Review Red was removed from gene: PYCR2
Intellectual disability v3.831 CEP63 Catherine Snow Source: Expert Review Red was removed from gene: CEP63
Intellectual disability v3.831 PYCR1 Ivone Leong Source: Expert Review Red was removed from gene: PYCR1
Intellectual disability v3.830 CD96 Catherine Snow Source: Expert Review Red was removed from gene: CD96
Intellectual disability v3.829 PUS1 Ivone Leong Source: Expert Review Red was removed from gene: PUS1
Intellectual disability v3.828 C9orf72 Catherine Snow Source: Expert Review Amber was removed from gene: C9orf72
Intellectual disability v3.828 PUF60 Ivone Leong Source: Expert Review Red was removed from gene: PUF60
Intellectual disability v3.827 PEX11B Ivone Leong Source: Expert Review Red was removed from gene: PEX11B
Intellectual disability v3.827 BEAN1 Catherine Snow Source: Expert Review Amber was removed from gene: BEAN1
Intellectual disability v3.826 NTRK1 Ivone Leong Source: Expert Review Red was removed from gene: NTRK1
Intellectual disability v3.826 CRYBA4 Sarah Leigh Source: Expert Review Amber was removed from gene: CRYBA4
Intellectual disability v3.825 NFIA Ivone Leong Source: Expert Review Red was removed from gene: NFIA
Intellectual disability v3.824 ATXN7 Catherine Snow Source: Expert Review Amber was removed from gene: ATXN7
Intellectual disability v3.823 ATXN3 Catherine Snow Source: Expert Review Amber was removed from gene: ATXN3
Intellectual disability v3.822 ATXN2 Catherine Snow Source: Expert Review Amber was removed from gene: ATXN2
Intellectual disability v3.821 ATXN10 Catherine Snow Source: Expert Review Amber was removed from gene: ATXN10
Intellectual disability v3.820 ATXN1 Catherine Snow Source: Expert Review Amber was removed from gene: ATXN1
Intellectual disability v3.819 NDST1 Ivone Leong Source: Expert Review Red was removed from gene: NDST1
Intellectual disability v3.817 UNC80 Catherine Snow Source: Expert Review Amber was removed from gene: UNC80
Intellectual disability v3.816 LONP1 Ivone Leong Source: Expert Review Red was removed from gene: LONP1
Intellectual disability v3.815 KMT2C Ivone Leong Source: Expert Review Red was removed from gene: KMT2C
Intellectual disability v3.815 UBA5 Catherine Snow Source: Expert Review Amber was removed from gene: UBA5
Intellectual disability v3.814 CDC45 Sarah Leigh Source: Expert Review Amber was removed from gene: CDC45
Intellectual disability v3.813 IER3IP1 Ivone Leong Source: Expert Review Red was removed from gene: IER3IP1
Intellectual disability v3.812 TRMT10A Catherine Snow Source: Expert Review Amber was removed from gene: TRMT10A
Intellectual disability v3.812 HIVEP2 Ivone Leong Source: Expert Review Red was removed from gene: HIVEP2
Intellectual disability v3.811 TMEM240 Catherine Snow Source: Expert Review Amber was removed from gene: TMEM240
Intellectual disability v3.810 GMPPB Ivone Leong Source: Expert Review Red was removed from gene: GMPPB
Intellectual disability v3.810 TBCD Catherine Snow Source: Expert Review Amber was removed from gene: TBCD
Intellectual disability v3.809 GFER Ivone Leong Source: Expert Review Red was removed from gene: GFER
Intellectual disability v3.808 EMX2 Ivone Leong Source: Expert Review Red was removed from gene: EMX2
Intellectual disability v3.808 SPTBN2 Catherine Snow Source: Expert Review Amber was removed from gene: SPTBN2
Intellectual disability v3.807 ELP2 Ivone Leong Source: Expert Review Red was removed from gene: ELP2
Intellectual disability v3.806 DNAJC19 Ivone Leong Source: Expert Review Red was removed from gene: DNAJC19
Intellectual disability v3.805 DAG1 Ivone Leong Source: Expert Review Red was removed from gene: DAG1
Intellectual disability v3.803 CRADD Ivone Leong Source: Expert Review Red was removed from gene: CRADD
Intellectual disability v3.803 SPART Catherine Snow Source: Expert Review Amber was removed from gene: SPART
Intellectual disability v3.802 COG5 Ivone Leong Source: Expert Review Red was removed from gene: COG5
Intellectual disability v3.801 SON Catherine Snow Source: Expert Review Amber was removed from gene: SON
Intellectual disability v3.801 CLCN4 Ivone Leong Source: Expert Review Red was removed from gene: CLCN4
Intellectual disability v3.800 CHMP1A Ivone Leong Source: Expert Review Red was removed from gene: CHMP1A
Intellectual disability v3.800 CCDC115 Sarah Leigh Source: Expert Review Amber was removed from gene: CCDC115
Intellectual disability v3.798 CAMK2A Ivone Leong Source: Expert Review Red was removed from gene: CAMK2A
Intellectual disability v3.798 PRUNE1 Catherine Snow Source: Expert Review Amber was removed from gene: PRUNE1
Intellectual disability v3.797 CACNA1S Sarah Leigh Source: Expert Review Amber was removed from gene: CACNA1S
Intellectual disability v3.797 CACNA1D Ivone Leong Source: Expert Review Red was removed from gene: CACNA1D
Intellectual disability v3.796 CACNA1A Ivone Leong Source: Expert Review Red was removed from gene: CACNA1A
Intellectual disability v3.795 PGAP1 Catherine Snow Source: Expert Review Amber was removed from gene: PGAP1
Intellectual disability v3.795 BRCA2 Sarah Leigh Source: Expert Review Amber was removed from gene: BRCA2
Intellectual disability v3.794 BSCL2 Ivone Leong Source: Expert Review Red was removed from gene: BSCL2
Intellectual disability v3.792 PNPLA6 Catherine Snow Source: Expert Review Amber was removed from gene: PNPLA6
Intellectual disability v3.791 ATP6V0A2 Ivone Leong Source: Expert Review Red was removed from gene: ATP6V0A2
Intellectual disability v3.790 PDE4D Catherine Snow Source: Expert Review Amber was removed from gene: PDE4D
Intellectual disability v3.789 ASL Ivone Leong Source: Expert Review Red was removed from gene: ASL
Intellectual disability v3.789 ATP7B Sarah Leigh Source: Expert Review Amber was removed from gene: ATP7B
Intellectual disability v3.787 PARN Catherine Snow Source: Expert Review Amber was removed from gene: PARN
Intellectual disability v3.787 ARL13B Ivone Leong Source: Expert Review Red was removed from gene: ARL13B
Intellectual disability v3.786 ARID2 Ivone Leong Source: Expert Review Red was removed from gene: ARID2
Intellectual disability v3.785 OPA3 Catherine Snow Source: Expert Review Amber was removed from gene: OPA3
Intellectual disability v3.784 AP3B1 Ivone Leong Source: Expert Review Red was removed from gene: AP3B1
Intellectual disability v3.783 PMP22 Arina Puzriakova Source: Expert Review Amber was removed from gene: PMP22
Intellectual disability v3.782 ADK Ivone Leong Source: Expert Review Red was removed from gene: ADK
Intellectual disability v3.781 CCDC186 Sarah Leigh Classified gene: CCDC186 as Amber List (moderate evidence)
Intellectual disability v3.781 CCDC186 Sarah Leigh Gene: ccdc186 has been classified as Amber List (Moderate Evidence).
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 Classified gene: ADAM22 as Amber List (moderate evidence)
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 v3.778 ADAM22 Sarah Leigh Gene: adam22 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.777 KCNN2 Arina Puzriakova Classified gene: KCNN2 as Amber List (moderate evidence)
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 v3.777 KCNN2 Arina Puzriakova Gene: kcnn2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.776 KCNN2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: KCNN2.
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 v3.776 SATB1 Arina Puzriakova Publications for gene: SATB1 were set to 33057194
Intellectual disability v3.775 SATB1 Arina Puzriakova Deleted their comment
Intellectual disability v3.775 SATB1 Arina Puzriakova Classified gene: SATB1 as Amber List (moderate evidence)
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 Gene: satb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.775 SATB1 Arina Puzriakova Classified gene: SATB1 as Amber List (moderate evidence)
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 Gene: satb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.774 SATB1 Arina Puzriakova Tag watchlist was removed from gene: SATB1.
Tag Q2_21_rating tag was added to gene: SATB1.
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 Classified gene: OTUD5 as Amber List (moderate evidence)
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 v3.774 OTUD5 Arina Puzriakova Gene: otud5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.773 OTUD5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: OTUD5.
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 Tag founder-effect tag was added to gene: PIGF.
Intellectual disability v3.773 PIGF Arina Puzriakova Classified gene: PIGF as Red List (low evidence)
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 v3.773 PIGF Arina Puzriakova Gene: pigf has been classified as Red List (Low Evidence).
Intellectual disability v3.772 OTUD5 Arina Puzriakova Publications for gene: OTUD5 were set to 33131077
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 Classified gene: METAP1 as Red List (low evidence)
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 v3.770 METAP1 Arina Puzriakova Gene: metap1 has been classified as Red List (Low Evidence).
Intellectual disability v3.769 HPDL Arina Puzriakova Classified gene: HPDL as Amber List (moderate evidence)
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 v3.769 HPDL Arina Puzriakova Gene: hpdl has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.768 HPDL Arina Puzriakova Publications for gene: HPDL were set to PMID: 32707086; 33188300
Intellectual disability v3.767 HPDL Arina Puzriakova Tag Q2_21_rating tag was added to gene: HPDL.
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 Classified gene: HIRA as Amber List (moderate evidence)
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 v3.766 HIRA Arina Puzriakova Gene: hira has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.765 HIRA Arina Puzriakova Tag watchlist tag was added to gene: HIRA.
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 Classified gene: B4GALNT1 as Green List (high evidence)
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 v3.764 B4GALNT1 Sarah Leigh Gene: b4galnt1 has been classified as Green List (High Evidence).
Intellectual disability v3.763 B4GALNT1 Sarah Leigh Publications for gene: B4GALNT1 were set to
Intellectual disability v3.762 B4GALNT1 Sarah Leigh Phenotypes for gene: B4GALNT1 were changed from ID; Spastic paraplegia 26, autosomal recessive to Spastic paraplegia 26, autosomal recessive OMIM:609195; hereditary spastic paraplegia 26 MONDO:0012213
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 v3.761 DDX58 Arina Puzriakova Mode of inheritance for gene: DDX58 was changed from to 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 v3.760 TCTN3 Arina Puzriakova Publications for gene: TCTN3 were set to
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 Classified gene: TCTN3 as Amber List (moderate evidence)
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 v3.759 TCTN3 Arina Puzriakova Gene: tctn3 has been classified as Amber List (Moderate Evidence).
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 v3.757 PRUNE1 Eleanor Williams Publications for gene: PRUNE1 were set to 26539891; 28334956
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 TCTN3 Arina Puzriakova Tag for-review tag was added to gene: TCTN3.
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 Classified gene: VPS4A as Amber List (moderate evidence)
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 v3.756 VPS4A Arina Puzriakova Gene: vps4a has been classified as Amber List (Moderate Evidence).
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 v3.755 VPS4A Arina Puzriakova Mode of inheritance for gene: VPS4A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v3.754 VPS4A Ivone Leong Tag for-review tag was added to gene: VPS4A.
Intellectual disability v3.754 VPS4A Ivone Leong Classified gene: VPS4A as Amber List (moderate evidence)
Intellectual disability v3.754 VPS4A Ivone Leong Gene: vps4a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.753 VPS4A Ivone Leong Publications for gene: VPS4A were set to (PMID: 33186545; 33186543; 33460484)
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 Tag for-review tag was added to gene: ADAM22.
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 v3.751 TET3 Sarah Leigh Phenotypes for gene: TET3 were changed from Beck-Fahrner syndrome 618798 to Beck-Fahrner syndrome OMIM:618798
Intellectual disability v3.751 TET3 Sarah Leigh Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007; 31928709
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 v3.749 MSMO1 Arina Puzriakova Phenotypes for gene: MSMO1 were changed from Microcephaly, congenital cataract, and psoriasiform dermatitis, 616834 to Microcephaly, congenital cataract, and psoriasiform dermatitis, OMIM:616834; Microcephaly-congenital cataract-psoriasiform dermatitis syndrome, MONDO:0014793
Intellectual disability v3.748 MEIS2 Arina Puzriakova Phenotypes for gene: MEIS2 were changed from Cleft palate, cardiac defects, and mental retardation; Oral cleft; Abnormal heart morphology; Intellectual disability; Cleft palate, cardiac defects, and mental retardation, 600987 to Cleft palate, cardiac defects, and mental retardation, OMIM:600987; Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies, MONDO:0010970
Intellectual disability v3.747 KNL1 Arina Puzriakova Phenotypes for gene: KNL1 were changed from Microcephaly 4, primary, autosomal recessive 604321 to Microcephaly 4, primary, autosomal recessive, OMIM:604321; Microcephaly 4, primary, autosomal recessive, MONDO:0011437
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 Classified gene: TOR1A as Amber List (moderate evidence)
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 v3.745 TOR1A Arina Puzriakova Gene: tor1a has been classified as Amber List (Moderate Evidence).
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 v3.744 TOR1A Arina Puzriakova Tag for-review tag was added to gene: TOR1A.
Intellectual disability v3.744 TOR1A Arina Puzriakova Publications for gene: TOR1A were set to 24896178
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 v3.743 TOR1A Arina Puzriakova Mode of inheritance for gene: TOR1A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
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 ABCC9 Arina Puzriakova Tag for-review was removed from gene: ABCC9.
Intellectual disability v3.740 UBR7 Arina Puzriakova Tag for-review tag was added to gene: UBR7.
Intellectual disability v3.740 UBR7 Arina Puzriakova Classified gene: UBR7 as Amber List (moderate evidence)
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 v3.740 UBR7 Arina Puzriakova Gene: ubr7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.739 UBR7 Arina Puzriakova Publications for gene: UBR7 were set to 21937992
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 Classified gene: RNU7-1 as Amber List (moderate evidence)
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 v3.737 RNU7-1 Arina Puzriakova Gene: rnu7-1 has been classified as Amber List (Moderate Evidence).
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 RNU7-1 Arina Puzriakova Tag for-review tag was added to gene: RNU7-1.
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 v3.734 FGFR1 Arina Puzriakova Phenotypes for gene: FGFR1 were changed from Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600 to Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600; Encephalocraniocutaneous lipomatosis, somatic mosaic, OMIM:613001
Intellectual disability v3.733 FGFR1 Arina Puzriakova Publications for gene: FGFR1 were set to 28825856
Intellectual disability v3.732 FGFR1 Arina Puzriakova Phenotypes for gene: FGFR1 were changed from Encephalocraniocutaneous lipomatosis, 613001; KALLMANN SYNDROME TYPE 2; Pfeiffer syndrome,101600 to Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600
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 Classified gene: TANC2 as Amber List (moderate evidence)
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 v3.731 TANC2 Arina Puzriakova Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.730 TANC2 Arina Puzriakova Publications for gene: TANC2 were set to 26350204; 31616000
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 Tag watchlist was removed from gene: TANC2.
Tag for-review tag was added to gene: TANC2.
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 Publications for gene: ATP1A3 were set to 22842232; 29396171; 29291920; 22842232; 28969699
Intellectual disability v3.729 ATP1A3 Arina Puzriakova Classified gene: ATP1A3 as Amber List (moderate evidence)
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 v3.729 ATP1A3 Arina Puzriakova Gene: atp1a3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.728 LAMB2 Zornitza Stark edited their review of gene: LAMB2: Changed rating: GREEN
Intellectual disability v3.728 PPIL1 Arina Puzriakova Tag for-review tag was added to gene: PPIL1.
Intellectual disability v3.728 PPIL1 Arina Puzriakova Classified gene: PPIL1 as Amber List (moderate evidence)
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 v3.728 PPIL1 Arina Puzriakova Gene: ppil1 has been classified as Amber List (Moderate Evidence).
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 Classified gene: FGF13 as Amber List (moderate evidence)
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 v3.726 FGF13 Arina Puzriakova Gene: fgf13 has been classified as Amber List (Moderate Evidence).
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 v3.723 FBRSL1 Arina Puzriakova Phenotypes for gene: FBRSL1 were changed from Intellectual disability; congenital anomalies to Intellectual disability; Microcephaly; Heart defect; Cleft palate; Contractures; Hearing impairment; Skin creases
Intellectual disability v3.722 FBRSL1 Arina Puzriakova Classified gene: FBRSL1 as Amber List (moderate evidence)
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 v3.722 FBRSL1 Arina Puzriakova Gene: fbrsl1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.721 FBRSL1 Arina Puzriakova Tag for-review tag was added to gene: FBRSL1.
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 Classified gene: DPH2 as Amber List (moderate evidence)
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 v3.721 DPH2 Arina Puzriakova Gene: dph2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.720 CDC40 Arina Puzriakova Tag watchlist tag was added to gene: CDC40.
Intellectual disability v3.720 CDC40 Arina Puzriakova Classified gene: CDC40 as Red List (low 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 v3.720 CDC40 Arina Puzriakova Gene: cdc40 has been classified as Red List (Low Evidence).
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 Classified gene: ABCC9 as Green List (high evidence)
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 v3.718 ABCC9 Arina Puzriakova Gene: abcc9 has been classified as Green List (High Evidence).
Intellectual disability v3.717 ABCC9 Arina Puzriakova Tag for-review tag was added to gene: ABCC9.
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 v3.717 TMEM260 Arina Puzriakova Mode of inheritance for gene: TMEM260 was changed from to 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 v3.715 TRAPPC12 Arina Puzriakova Publications for gene: TRAPPC12 were set to 28777934
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 SMG8 Ivone Leong Tag for-review tag was added to gene: SMG8.
Intellectual disability v3.714 NUP214 Arina Puzriakova Tag for-review was removed from gene: NUP214.
Intellectual disability v3.714 NARS Ivone Leong Tag for-review tag was added to gene: NARS.
Intellectual disability v3.714 FGF13 Helen Lord Deleted their review
Intellectual disability v3.714 FGF13 Helen Lord commented on gene: FGF13
Intellectual disability v3.714 GLS_GCA Arina Puzriakova Tag NGS Not Validated tag was added to STR: GLS_GCA.
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 Classified STR: GLS_GCA as Red List (low evidence)
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 v3.714 GLS_GCA Arina Puzriakova Str: gls_gca has been classified as Red List (Low Evidence).
Intellectual disability v3.713 GLS_GCA Arina Puzriakova Tag STR tag was added to STR: GLS_GCA.
Tag for-review tag was added to STR: GLS_GCA.
Intellectual disability v3.713 GLS Arina Puzriakova Deleted their comment
Intellectual disability v3.713 GLS Arina Puzriakova Tag STR tag was added to gene: GLS.
Tag for-review tag was added to gene: GLS.
Intellectual disability v3.713 GLS Arina Puzriakova Classified gene: GLS as Amber List (moderate evidence)
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 v3.713 GLS Arina Puzriakova Gene: gls has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.712 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Intellectual disability v3.712 GLS Arina Puzriakova Added comment: Comment on phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685
Intellectual disability v3.712 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412
Intellectual disability v3.711 GLS Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733
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 v3.710 GLS Arina Puzriakova Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
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 v3.707 KIF14 Arina Puzriakova Phenotypes for gene: KIF14 were changed from Microcephaly 20, primary, autosomal recessive, 617914 to Microcephaly 20, primary, autosomal recessive, OMIM:617914; Microcephaly 20, primary, autosomal recessive, MONDO:0054761
Intellectual disability v3.706 B9D1 Arina Puzriakova Phenotypes for gene: B9D1 were changed from ?Meckel syndrome 9 614209; Joubert syndrome 27 617120 to Meckel syndrome 9, OMIM:614209; Meckel syndrome 9, MONDO:0013630; Joubert syndrome 27, OMIM:617120; Joubert syndrome 27, MONDO:0014927
Intellectual disability v3.705 B9D2 Arina Puzriakova Phenotypes for gene: B9D2 were changed from Joubert syndrome 34 614175; Meckel syndrome 10 614175 to Joubert syndrome 34, OMIM:614175; Meckel syndrome 10, OMIM:614175; Meckel syndrome, type 10, MONDO:0013609
Intellectual disability v3.704 EEF1A2 Eleanor Williams Tag for-review was removed from gene: EEF1A2.
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 Classified gene: ALKBH8 as Green List (high evidence)
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 v3.703 ALKBH8 Ivone Leong Gene: alkbh8 has been classified as Green List (High Evidence).
Intellectual disability v3.702 ALKBH8 Ivone Leong Tag for-review tag was added to gene: ALKBH8.
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 v3.702 NUS1 Eleanor Williams Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.701 NUS1 Eleanor Williams Classified gene: NUS1 as Amber List (moderate evidence)
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 v3.701 NUS1 Eleanor Williams Gene: nus1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.700 TLK2 Arina Puzriakova Phenotypes for gene: TLK2 were changed from intellectual disability to Mental retardation, autosomal dominant 57, OMIM:618050; Mental retardation, autosomal dominant 57, MONDO:0054837
Intellectual disability v3.699 ZNF526 Arina Puzriakova Classified gene: ZNF526 as Amber List (moderate evidence)
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 v3.699 ZNF526 Arina Puzriakova Gene: znf526 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.698 ZNF526 Arina Puzriakova Phenotypes for gene: ZNF526 were changed from Non-syndromic autosomal recessive intellectual disability to Intellectual disability; Microcephaly; Cataracts; Epilepsy; Hypertonia; Dystonia
Intellectual disability v3.697 ZNF526 Arina Puzriakova Publications for gene: ZNF526 were set to 21937992; 27012031
Intellectual disability v3.696 ZNF526 Arina Puzriakova Tag for-review tag was added to gene: ZNF526.
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 v3.696 TUBB2A Arina Puzriakova Publications for gene: TUBB2A were set to 24702957
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 RNU7-1 Zornitza Stark gene: RNU7-1 was added
gene: RNU7-1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Aicardi–Goutières syndrome-like
Review for gene: RNU7-1 was set to GREEN
gene: RNU7-1 was marked as current diagnostic
Added comment: Review originally submitted by Ming Wong
- 16 affected individuals from 11 families
- Compared to control fibroblasts, patient fibroblasts were enriched for misprocessed forms of
replication-dependent histone (RDH) mRNAs
Sources: Literature
Intellectual disability 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 commented on gene: CCDC40: PMID 33220177, provided in error, refers to CDC40.
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 v3.694 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, 613744; CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 4 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Intellectual disability v3.693 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, 614066; CEREBRAL PALSY SPASTIC QUADRIPLEGIC TYPE 5 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
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 Tag watchlist tag was added to gene: SLC9A7.
Intellectual disability v3.690 SLC9A7 Arina Puzriakova Classified gene: SLC9A7 as Amber List (moderate evidence)
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 v3.690 SLC9A7 Arina Puzriakova Gene: slc9a7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.689 SLC9A7 Arina Puzriakova Phenotypes for gene: SLC9A7 were changed from Intellectual developmental disorder, X-linked 108; OMIM #301024 to Intellectual developmental disorder, X-linked 108, OMIM:301024; Intellectual developmental disorder, X-linked 108, MONDO:0026723
Intellectual disability v3.688 MPI Arina Puzriakova Publications for gene: MPI were set to 9525984; 3080572; 9585601
Intellectual disability v3.687 MPI Arina Puzriakova Phenotypes for gene: MPI were changed from CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257
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 MPI Arina Puzriakova Tag for-review tag was added to gene: MPI.
Intellectual disability v3.686 HDAC4 Arina Puzriakova commented on gene: HDAC4
Intellectual disability v3.686 HDAC4 Arina Puzriakova Tag for-review was removed from gene: HDAC4.
Intellectual disability v3.686 AGO2 Arina Puzriakova Classified gene: AGO2 as Amber List (moderate evidence)
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 v3.686 AGO2 Arina Puzriakova Gene: ago2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.685 AGO2 Arina Puzriakova Tag for-review tag was added to gene: AGO2.
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 Classified gene: ZNF407 as Amber List (moderate evidence)
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 v3.685 ZNF407 Arina Puzriakova Gene: znf407 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.684 SMG8 Arina Puzriakova Phenotypes for gene: SMG8 were changed from Intellectual disability; Microcephaly; Short stature; Facial dysmorphism Edit to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism
Intellectual disability v3.684 SMG8 Arina Puzriakova Phenotypes for gene: SMG8 were changed from Intellectual disability to Intellectual disability; Microcephaly; Short stature; Facial dysmorphism Edit
Intellectual disability v3.683 SMG8 Arina Puzriakova Classified gene: SMG8 as Amber List (moderate evidence)
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 v3.683 SMG8 Arina Puzriakova Gene: smg8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.682 SMG8 Arina Puzriakova Publications for gene: SMG8 were set to 31130284
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 Tag for-review tag was added to gene: LSS.
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 v3.680 KCNMA1 Arina Puzriakova Publications for gene: KCNMA1 were set to 15937479; 31427379; 31152168; 27567911; 29545233; 26195193
Intellectual disability v3.679 KCNMA1 Arina Puzriakova Classified gene: KCNMA1 as Amber List (moderate evidence)
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 v3.679 KCNMA1 Arina Puzriakova Gene: kcnma1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.678 KCNMA1 Arina Puzriakova Tag for-review tag was added to gene: KCNMA1.
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 LIAS Eleanor Williams commented on gene: LIAS
Intellectual disability v3.678 LIAS Eleanor Williams Tag for-review tag was added to gene: LIAS.
Intellectual disability v3.678 GRIA1 Arina Puzriakova Classified gene: GRIA1 as Amber List (moderate evidence)
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 v3.678 GRIA1 Arina Puzriakova Gene: gria1 has been classified as Amber List (Moderate Evidence).
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 v3.677 H3F3B Arina Puzriakova Publications for gene: H3F3B were set to
Intellectual disability v3.676 H3F3B Arina Puzriakova Phenotypes for gene: H3F3B were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Intellectual disability v3.675 H3F3B Arina Puzriakova Mode of inheritance for gene: H3F3B was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.674 H3F3B Arina Puzriakova Classified gene: H3F3B as Amber List (moderate evidence)
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 v3.674 H3F3B Arina Puzriakova Gene: h3f3b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.673 H3F3B Arina Puzriakova Tag for-review tag was added to gene: H3F3B.
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 v3.673 H3F3A Arina Puzriakova Phenotypes for gene: H3F3A were changed from to Developmental delay; Intellectual disability; Neurodegeneration; Epilepsy; Facial dysmorphism; Congenital anomalies
Intellectual disability v3.672 H3F3A Arina Puzriakova Publications for gene: H3F3A were set to
Intellectual disability v3.671 H3F3A Arina Puzriakova Mode of inheritance for gene: H3F3A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.670 H3F3A Arina Puzriakova Deleted their comment
Intellectual disability v3.670 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
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 Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.670 H3F3A Arina Puzriakova Classified gene: H3F3A as Amber List (moderate evidence)
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 Gene: h3f3a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.669 H3F3A Arina Puzriakova Tag for-review tag was added to gene: H3F3A.
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 Tag for-review tag was added to gene: KDM4B.
Intellectual disability v3.669 KDM4B Arina Puzriakova Classified gene: KDM4B as Amber List (moderate evidence)
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 v3.669 KDM4B Arina Puzriakova Gene: kdm4b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.668 HSPG2 Arina Puzriakova Phenotypes for gene: HSPG2 were changed from Schwartz-Jampel syndrome, type 1, 255800 to Schwartz-Jampel syndrome, type 1, OMIM:255800; Schwartz-Jampel syndrome, MONDO:0009717
Intellectual disability v3.667 HSPG2 Arina Puzriakova Classified gene: HSPG2 as Amber List (moderate evidence)
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 v3.667 HSPG2 Arina Puzriakova Gene: hspg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.666 CSNK1G1 Arina Puzriakova Classified gene: CSNK1G1 as Amber List (moderate evidence)
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 v3.666 CSNK1G1 Arina Puzriakova Gene: csnk1g1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.665 CSNK1G1 Arina Puzriakova Tag for-review tag was added to gene: CSNK1G1.
Intellectual disability v3.665 SHMT2 Arina Puzriakova Tag for-review tag was added to gene: SHMT2.
Intellectual disability v3.665 SHMT2 Arina Puzriakova Classified gene: SHMT2 as Amber List (moderate evidence)
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 v3.665 SHMT2 Arina Puzriakova Gene: shmt2 has been classified as Amber List (Moderate Evidence).
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 v3.663 ITFG2 Arina Puzriakova Publications for gene: ITFG2 were set to 28397838; https://doi.org/10.1038/s41525-020-00150-z
Intellectual disability v3.662 ITFG2 Arina Puzriakova Classified gene: ITFG2 as Amber List (moderate evidence)
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 v3.662 ITFG2 Arina Puzriakova Gene: itfg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.661 RAP1B Ivone Leong Tag watchlist tag was added to gene: RAP1B.
Intellectual disability v3.661 RAP1B Ivone Leong Classified gene: RAP1B as Amber List (moderate evidence)
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 v3.661 RAP1B Ivone Leong Gene: rap1b has been classified as Amber List (Moderate Evidence).
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 v3.660 AASS Arina Puzriakova Phenotypes for gene: AASS were changed from HYPERLYSINEMIA to Hyperlysinemia, OMIM:238700; Hyperlysinemia (disease), MONDO:0009388
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 v3.658 AAAS Arina Puzriakova Phenotypes for gene: AAAS were changed from Achalasia-addisonianism-alacrimia syndrome 231550 to Achalasia-addisonianism-alacrimia syndrome, OMIM:231550; Triple-A syndrome, MONDO:0009279
Intellectual disability v3.657 GOT2 Arina Puzriakova Tag watchlist was removed from gene: GOT2.
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 Classified gene: GOT2 as Amber List (moderate evidence)
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 v3.656 GOT2 Arina Puzriakova Gene: got2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.655 GOT2 Arina Puzriakova commented on gene: GOT2
Intellectual disability v3.655 GATA6 Arina Puzriakova Classified gene: GATA6 as Amber List (moderate evidence)
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 v3.655 GATA6 Arina Puzriakova Gene: gata6 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.654 HS2ST1 Ivone Leong Tag watchlist tag was added to gene: HS2ST1.
Intellectual disability v3.654 HS2ST1 Ivone Leong Classified gene: HS2ST1 as Amber List (moderate evidence)
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 v3.654 HS2ST1 Ivone Leong Gene: hs2st1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.653 BICRA Ivone Leong Classified gene: BICRA as Amber List (moderate evidence)
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 v3.653 BICRA Ivone Leong Gene: bicra has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.652 BICRA Ivone Leong Tag for-review tag was added to gene: BICRA.
Intellectual disability v3.652 EMC10 Ivone Leong Classified gene: EMC10 as Red List (low evidence)
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 v3.652 EMC10 Ivone Leong Gene: emc10 has been classified as Red List (Low Evidence).
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 v3.650 CSNK1G1 Ivone Leong Publications for gene: CSNK1G1 were set to 24463883
Intellectual disability v3.649 GATA6 Ivone Leong Publications for gene: GATA6 were set to
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 commented on gene: NARS: Added new-gene-name tag, new approved HGNC gene symbol for NARS is NARS1
Intellectual disability v3.648 NARS Arina Puzriakova Classified gene: NARS as Amber List (moderate evidence)
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 v3.648 NARS Arina Puzriakova Gene: nars has been classified as Amber List (Moderate Evidence).
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 v3.647 NARS Arina Puzriakova Publications for gene: NARS were set to 32738225
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 AGO2 Zornitza Stark gene: AGO2 was added
gene: AGO2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AGO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AGO2 were set to 33199684
Phenotypes for gene: AGO2 were set to Intellectual disability; regression; seizures
Review for gene: AGO2 was set to GREEN
Added comment: 21 individuals reported, five variants (p.L192P, p.G201V, p.T357M, p.M364T, p.C751Y) were recurrent. Variable ID.
Sources: Literature
Intellectual disability 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 v3.644 ATP2A2 Ivone Leong Publications for gene: ATP2A2 were set to 19250991; 20456342
Intellectual disability v3.643 SMARCA2 Arina Puzriakova Phenotypes for gene: SMARCA2 were changed from Nicolaides-Baraitser syndrome, 601358; COFFIN SIRIS to Nicolaides-Baraitser syndrome, OMIM:601358; Coffin-siris syndrome; Blepharophimosis intellectual disability syndrome
Intellectual disability v3.642 SMARCA2 Arina Puzriakova Publications for gene: SMARCA2 were set to
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 v3.640 MORC2 Arina Puzriakova Publications for gene: MORC2 were set to https://doi.org/10.1016/j.ajhg.2020.06.013
Intellectual disability v3.639 MORC2 Arina Puzriakova Classified gene: MORC2 as Amber List (moderate evidence)
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 v3.639 MORC2 Arina Puzriakova Gene: morc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.638 MORC2 Arina Puzriakova Tag for-review tag was added to gene: MORC2.
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 commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Intellectual disability v3.638 LARS Arina Puzriakova Classified gene: LARS as Amber List (moderate evidence)
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 v3.638 LARS Arina Puzriakova Gene: lars has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.637 LARS Arina Puzriakova Tag new-gene-name tag was added to gene: LARS.
Tag for-review tag was added to gene: LARS.
Intellectual disability v3.637 NUS1 Arina Puzriakova Classified gene: NUS1 as Amber List (moderate evidence)
Intellectual disability v3.637 NUS1 Arina Puzriakova Gene: nus1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.636 NUS1 Arina Puzriakova Tag for-review tag was added to gene: NUS1.
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 v3.635 SOX3 Arina Puzriakova commented on gene: SOX3
Intellectual disability v3.635 SOX3 Arina Puzriakova Tag for-review tag was added to gene: SOX3.
Intellectual disability v3.635 PSAT1 Arina Puzriakova Publications for gene: PSAT1 were set to 17436247
Intellectual disability v3.634 PSAT1 Arina Puzriakova Phenotypes for gene: PSAT1 were changed from PHOSPHOSERINE AMINOTRANSFERASE DEFICIENCY to Phosphoserine aminotransferase deficiency, OMIM:610992; Neu-Laxova syndrome 2, OMIM:616038
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 Classified gene: SH3PXD2B as Red List (low evidence)
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 v3.632 SH3PXD2B Arina Puzriakova Gene: sh3pxd2b has been classified as Red List (Low Evidence).
Intellectual disability v3.631 SEC23B Arina Puzriakova Classified gene: SEC23B as Red List (low evidence)
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 v3.631 SEC23B Arina Puzriakova Gene: sec23b has been classified as Red List (Low Evidence).
Intellectual disability v3.630 SCN11A Arina Puzriakova Classified gene: SCN11A as Red List (low evidence)
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 v3.630 SCN11A Arina Puzriakova Gene: scn11a has been classified as Red List (Low Evidence).
Intellectual disability v3.629 SCARF2 Arina Puzriakova Classified gene: SCARF2 as Red List (low evidence)
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 v3.629 SCARF2 Arina Puzriakova Gene: scarf2 has been classified as Red List (Low Evidence).
Intellectual disability v3.628 SBDS Arina Puzriakova Classified gene: SBDS as Red List (low evidence)
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 v3.628 SBDS Arina Puzriakova Gene: sbds has been classified as Red List (Low Evidence).
Intellectual disability v3.627 SALL4 Arina Puzriakova Classified gene: SALL4 as Red List (low evidence)
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 v3.627 SALL4 Arina Puzriakova Gene: sall4 has been classified as Red List (Low Evidence).
Intellectual disability v3.626 PRSS56 Arina Puzriakova Classified gene: PRSS56 as Red List (low evidence)
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 v3.626 PRSS56 Arina Puzriakova Gene: prss56 has been classified as Red List (Low Evidence).
Intellectual disability v3.625 PROP1 Arina Puzriakova Classified gene: PROP1 as Red List (low evidence)
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 v3.625 PROP1 Arina Puzriakova Gene: prop1 has been classified as Red List (Low Evidence).
Intellectual disability v3.624 PRDM12 Arina Puzriakova Classified gene: PRDM12 as Red List (low evidence)
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 v3.624 PRDM12 Arina Puzriakova Gene: prdm12 has been classified as Red List (Low Evidence).
Intellectual disability v3.623 PPA2 Arina Puzriakova Classified gene: PPA2 as Red List (low evidence)
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 v3.623 PPA2 Arina Puzriakova Gene: ppa2 has been classified as Red List (Low Evidence).
Intellectual disability v3.622 POLR1D Arina Puzriakova Classified gene: POLR1D as Red List (low evidence)
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 v3.622 POLR1D Arina Puzriakova Gene: polr1d has been classified as Red List (Low Evidence).
Intellectual disability v3.621 POLD1 Arina Puzriakova Classified gene: POLD1 as Red List (low evidence)
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 v3.621 POLD1 Arina Puzriakova Gene: pold1 has been classified as Red List (Low Evidence).
Intellectual disability v3.620 POC1B Arina Puzriakova Classified gene: POC1B as Red List (low evidence)
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 v3.620 POC1B Arina Puzriakova Gene: poc1b has been classified as Red List (Low Evidence).
Intellectual disability v3.619 PMS2 Arina Puzriakova Classified gene: PMS2 as Red List (low evidence)
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 v3.619 PMS2 Arina Puzriakova Gene: pms2 has been classified as Red List (Low Evidence).
Intellectual disability v3.618 PLOD2 Arina Puzriakova Classified gene: PLOD2 as Red List (low evidence)
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 v3.618 PLOD2 Arina Puzriakova Gene: plod2 has been classified as Red List (Low Evidence).
Intellectual disability v3.617 PKHD1 Arina Puzriakova Classified gene: PKHD1 as Red List (low evidence)
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 v3.617 PKHD1 Arina Puzriakova Gene: pkhd1 has been classified as Red List (Low Evidence).
Intellectual disability v3.616 PKD1L1 Arina Puzriakova Classified gene: PKD1L1 as Red List (low evidence)
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 v3.616 PKD1L1 Arina Puzriakova Gene: pkd1l1 has been classified as Red List (Low Evidence).
Intellectual disability v3.615 PITX3 Arina Puzriakova Classified gene: PITX3 as Red List (low evidence)
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 v3.615 PITX3 Arina Puzriakova Gene: pitx3 has been classified as Red List (Low Evidence).
Intellectual disability v3.614 PITX2 Arina Puzriakova Classified gene: PITX2 as Red List (low evidence)
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 v3.614 PITX2 Arina Puzriakova Gene: pitx2 has been classified as Red List (Low Evidence).
Intellectual disability v3.613 PIK3R1 Arina Puzriakova Classified gene: PIK3R1 as Red List (low evidence)
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 v3.613 PIK3R1 Arina Puzriakova Gene: pik3r1 has been classified as Red List (Low Evidence).
Intellectual disability v3.612 POLR1C Arina Puzriakova Phenotypes for gene: POLR1C were changed from Treacher Collins syndrome 3, 248390 to Leukodystrophy, hypomyelinating, 11, OMIM:616494
Intellectual disability v3.611 POLR1C Arina Puzriakova Publications for gene: POLR1C were set to
Intellectual disability v3.610 POLR1C Arina Puzriakova Tag for-review tag was added to gene: POLR1C.
Intellectual disability v3.610 POLR1C Arina Puzriakova Classified gene: POLR1C as Amber List (moderate evidence)
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 v3.610 POLR1C Arina Puzriakova Gene: polr1c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.609 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; developmental delay; intellectual disability to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Combined oxidative phosphorylation defect type 13, MONDO:0013977
Intellectual disability v3.608 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
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 v3.608 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.607 SCN1B Arina Puzriakova Classified gene: SCN1B as Amber List (moderate evidence)
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 v3.607 SCN1B Arina Puzriakova Gene: scn1b has been classified as Amber List (Moderate Evidence).
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 v3.605 SCN1B Arina Puzriakova Publications for gene: SCN1B were set to 18464934
Intellectual disability v3.604 SCN1B Arina Puzriakova Mode of inheritance for gene: SCN1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.603 ZFHX4 Ivone Leong Publications for gene: ZFHX4 were set to 26350204; 21802062
Intellectual disability v3.602 ZFHX4 Ivone Leong Phenotypes for gene: ZFHX4 were changed from to Developmental disorders; intellectual disability, dysmorphic features
Intellectual disability v3.601 ZFHX4 Ivone Leong Classified gene: ZFHX4 as Amber List (moderate evidence)
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 v3.601 ZFHX4 Ivone Leong Gene: zfhx4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.600 ZFHX4 Ivone Leong Mode of inheritance for gene: ZFHX4 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.599 ZFHX4 Ivone Leong Tag for-review tag was added to gene: ZFHX4.
Intellectual disability v3.599 UPF1 Ivone Leong Classified gene: UPF1 as Amber List (moderate evidence)
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 v3.599 UPF1 Ivone Leong Gene: upf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.598 UPF1 Ivone Leong Publications for gene: UPF1 were set to 33057194
Intellectual disability v3.597 U2AF2 Ivone Leong Classified gene: U2AF2 as Amber List (moderate evidence)
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 v3.597 U2AF2 Ivone Leong Gene: u2af2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.596 TCF7L2 Ivone Leong Classified gene: TCF7L2 as Amber List (moderate evidence)
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 v3.596 TCF7L2 Ivone Leong Gene: tcf7l2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.595 SRRM2 Ivone Leong Classified gene: SRRM2 as Amber List (moderate evidence)
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 v3.595 SRRM2 Ivone Leong Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.594 SPEN Ivone Leong Classified gene: SPEN as Amber List (moderate evidence)
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 v3.594 SPEN Ivone Leong Gene: spen has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.593 SATB1 Ivone Leong Phenotypes for gene: SATB1 were changed from intellectual disability to intellectual disability; developmental disorders
Intellectual disability v3.592 SATB1 Ivone Leong Classified gene: SATB1 as Amber List (moderate evidence)
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 v3.592 SATB1 Ivone Leong Gene: satb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.591 SATB1 Ivone Leong Publications for gene: SATB1 were set to
Intellectual disability v3.590 MSL2 Ivone Leong Classified gene: MSL2 as Amber List (moderate 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 Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.590 MSL2 Ivone Leong Classified gene: MSL2 as Amber List (moderate 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 Gene: msl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.589 RAB14 Ivone Leong Classified gene: RAB14 as Amber List (moderate evidence)
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 v3.589 RAB14 Ivone Leong Gene: rab14 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.588 PSMC5 Ivone Leong Classified gene: PSMC5 as Amber List (moderate evidence)
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 v3.588 PSMC5 Ivone Leong Gene: psmc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.587 MMGT1 Ivone Leong Classified gene: MMGT1 as Amber List (moderate evidence)
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 v3.587 MMGT1 Ivone Leong Gene: mmgt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.586 HNRNPD Ivone Leong Classified gene: HNRNPD as Amber List (moderate evidence)
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 v3.586 HNRNPD Ivone Leong Gene: hnrnpd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.585 FBXO31 Ivone Leong Classified gene: FBXO31 as Amber List (moderate evidence)
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 v3.585 FBXO31 Ivone Leong Gene: fbxo31 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.584 FBXO31 Ivone Leong Tag watchlist tag was added to gene: FBXO31.
Intellectual disability v3.584 PIK3C2A Arina Puzriakova Classified gene: PIK3C2A as Amber List (moderate evidence)
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 v3.584 PIK3C2A Arina Puzriakova Gene: pik3c2a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.583 FBXO31 Ivone Leong Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, autosomal dominant to ?Mental retardation, autosomal recessive 45, OMIM:615979; Intellectual disability, autosomal dominant
Intellectual disability v3.582 FOXP4 Ivone Leong Classified gene: FOXP4 as Amber List (moderate evidence)
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 v3.582 FOXP4 Ivone Leong Gene: foxp4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.581 DHX32 Ivone Leong Classified gene: DHX32 as Amber List (moderate evidence)
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 v3.581 DHX32 Ivone Leong Gene: dhx32 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.580 GIGYF1 Ivone Leong Classified gene: GIGYF1 as Amber List (moderate evidence)
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 v3.580 GIGYF1 Ivone Leong Gene: gigyf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.579 ATP6V0A1 Ivone Leong Classified gene: ATP6V0A1 as Amber List (moderate evidence)
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 v3.579 ATP6V0A1 Ivone Leong Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.578 DDX23 Ivone Leong Classified gene: DDX23 as Amber List (moderate evidence)
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 v3.578 DDX23 Ivone Leong Gene: ddx23 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.577 DDX23 Ivone Leong Tag watchlist tag was added to gene: DDX23.
Intellectual disability v3.577 ARHGAP35 Ivone Leong Classified gene: ARHGAP35 as Amber List (moderate evidence)
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 v3.577 ARHGAP35 Ivone Leong Gene: arhgap35 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.576 ARHGAP35 Ivone Leong Tag watchlist tag was added to gene: ARHGAP35.
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 Classified gene: AP2S1 as Amber List (moderate evidence)
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 v3.575 AP2S1 Ivone Leong Gene: ap2s1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.574 AP2S1 Ivone Leong Tag watchlist tag was added to gene: AP2S1.
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 Tag Skewed X-inactivation tag was added to gene: TFE3.
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 v3.573 CDH2 Arina Puzriakova Phenotypes for gene: CDH2 were changed from Agenesis of corpus callosum, cardiac, ocular, and genital syndrome 618929 to Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, OMIM:618929; Agenesis of corpus callosum, cardiac, ocular, and genital syndrome, MONDO:0030065
Intellectual disability v3.572 CDH2 Arina Puzriakova Publications for gene: CDH2 were set to 31585109; 9015265; 17222817
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 v3.570 ISCA-37415-Gain Arina Puzriakova Publications for Region: ISCA-37415-Gain were set to 23637818; 24352232; 21614007
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 Classified gene: LMNB2 as Amber List (moderate evidence)
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 v3.566 LMNB2 Sarah Leigh Gene: lmnb2 has been classified as Amber List (Moderate Evidence).
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 v3.565 DDC Arina Puzriakova Publications for gene: DDC were set to 20505134
Intellectual disability v3.564 DDC Arina Puzriakova Phenotypes for gene: DDC were changed from AROMATIC L-AMINO-ACID DECARBOXYLASE DEFICIENCY to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Intellectual disability v3.563 AGAP1 Arina Puzriakova Classified gene: AGAP1 as Amber List (moderate evidence)
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 v3.563 AGAP1 Arina Puzriakova Gene: agap1 has been classified as Amber List (Moderate Evidence).
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 Classified gene: MPP5 as Amber List (moderate evidence)
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 v3.562 MPP5 Arina Puzriakova Gene: mpp5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.561 MPP5 Arina Puzriakova Tag for-review tag was added to gene: MPP5.
Intellectual disability v3.561 JARID2 Arina Puzriakova Classified gene: JARID2 as Amber List (moderate evidence)
Intellectual disability v3.561 JARID2 Arina