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Intellectual disability v3.1677 EMC1 Eleanor Williams Added comment: Comment on mode of inheritance: 3 more cases of monoallelic variants in patients with an intellectual disability phenotype now reported so the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'
Intellectual disability v3.1677 EMC1 Eleanor Williams Mode of inheritance for gene: EMC1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1676 EMC1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: EMC1.
Intellectual disability v3.1676 EMC1 Eleanor Williams commented on gene: EMC1
Intellectual disability v3.1676 CNKSR2 Eleanor Williams commented on gene: CNKSR2
Intellectual disability v3.1676 RAB11A Eleanor Williams changed review comment from: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.; to: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS, they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.
Intellectual disability v3.1676 RAB11A Eleanor Williams changed review comment from: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS they identified two different heterozygous missense variants in RAB11A in two unrelated patients. One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.; to: PMID: 33875846 - Bertoli-Avella et al 2021 - in a large study of patients with no initial diagnostic variants identified by ES/GS they identified two different heterozygous missense variants in RAB11A in two unrelated patients (NM_004663.4: c.375G>T, p. Lys125Asn and NM_004663.4: c.380A>G, p. Asp127Gly). One was de-novo. Little patient information but both had brain anomalies and intellectual disability reported. 1 had seizures.
Intellectual disability v3.1676 RAB11A Eleanor Williams Classified gene: RAB11A as Amber List (moderate evidence)
Intellectual disability v3.1676 RAB11A Eleanor Williams Added comment: Comment on list classification: Leaving the rating as amber just now, but with a recommendation of GREEN rating following GMS review. There are now 6 unrelated individuals with an intellectual disability phenotype reported and missense variants in this gene. Although there is little clinical data available the number of cases adds weight to this gene-disease association.
Intellectual disability v3.1676 RAB11A Eleanor Williams Gene: rab11a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1675 RAB11A Eleanor Williams Phenotypes for gene: RAB11A were changed from Global developmental delay; Global developmental delay, Intellectual disability; Intellectual disability to Global developmental delay, HP:0001263; Intellectual disability, HP:0001249
Intellectual disability v3.1674 RAB11A Eleanor Williams Publications for gene: RAB11A were set to 29100083
Intellectual disability v3.1673 RAB11A Eleanor Williams Tag Q3_22_rating tag was added to gene: RAB11A.
Intellectual disability v3.1673 RAB11A Eleanor Williams commented on gene: RAB11A
Intellectual disability v3.1673 FBXW7 Sarah Leigh edited their review of gene: FBXW7: Changed rating: GREEN
Intellectual disability v3.1673 FBXW7 Sarah Leigh Classified gene: FBXW7 as Amber List (moderate evidence)
Intellectual disability v3.1673 FBXW7 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 v3.1673 FBXW7 Sarah Leigh Gene: fbxw7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1672 FBXW7 Sarah Leigh Tag Q3_22_rating tag was added to gene: FBXW7.
Tag Q3_22_MOI tag was added to gene: FBXW7.
Tag Q3_22_phenotype tag was added to gene: FBXW7.
Intellectual disability v3.1672 FBXW7 Sarah Leigh commented on gene: FBXW7
Intellectual disability v3.1672 SLC35B2 Sarah Leigh Classified gene: SLC35B2 as Amber List (moderate evidence)
Intellectual disability v3.1672 SLC35B2 Sarah Leigh Added comment: Comment on list classification: The evidence for this gene is sufficient for an amber rating. Although supportive functional evidence is presented in PMID: 35325049, the presence of other variants in both cases reported in this article, means that further evidence is required for SLC35B2 to be rated Green.
Intellectual disability v3.1672 SLC35B2 Sarah Leigh Gene: slc35b2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1671 CNKSR2 Eleanor Williams Phenotypes for gene: CNKSR2 were changed from ntellectual developmental disorder, X-linked, syndromic, Houge type, OMIM:301008; intellectual disability, X-linked, syndromic, Houge type, MONDO:0030909 to Intellectual developmental disorder, X-linked, syndromic, Houge type, OMIM:301008; intellectual disability, X-linked, syndromic, Houge type, MONDO:0030909
Intellectual disability v3.1670 CNKSR2 Eleanor Williams Publications for gene: CNKSR2 were set to
Intellectual disability v3.1669 CNKSR2 Eleanor Williams Phenotypes for gene: CNKSR2 were changed from INTELLECTUAL DISABILITY WITH EPILEPSY; X-linked intellectual disability; XLID to ntellectual developmental disorder, X-linked, syndromic, Houge type, OMIM:301008; intellectual disability, X-linked, syndromic, Houge type, MONDO:0030909
Intellectual disability v3.1668 TPP2 Eleanor Williams commented on gene: TPP2: As the first presentation for patients is features of immune deficiency and autoimmunity, seeking clinical input before proposing a rating for this gene on the intellectual disability panel.
Intellectual disability v3.1668 TPP2 Eleanor Williams Publications for gene: TPP2 were set to
Intellectual disability v3.1667 TPP2 Eleanor Williams reviewed gene: TPP2: Rating: ; Mode of pathogenicity: None; Publications: 33586135, 25414442, 25525876, 30533531; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1667 TPP2 Eleanor Williams gene: TPP2 was added
gene: TPP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TPP2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TPP2 were set to Immunodeficiency 78 with autoimmunity and developmental delay, OMIM:619220
Intellectual disability v3.1666 TAF4 Eleanor Williams Classified gene: TAF4 as Amber List (moderate evidence)
Intellectual disability v3.1666 TAF4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. There are 3 cases reported but in one the phenotype is reported as autism, and in the other two there is no information as to the severity. The mouse knockout shows there is an effect of loss of TAF4 but the phenotype is perhaps not specific enough to add weight to rating of this gene for intellectual disability.
Intellectual disability v3.1666 TAF4 Eleanor Williams Gene: taf4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1665 TAF4 Eleanor Williams Mode of inheritance for gene: TAF4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1664 TAF4 Eleanor Williams Publications for gene: TAF4 were set to 33875846
Intellectual disability v3.1663 TAF4 Eleanor Williams Phenotypes for gene: TAF4 were changed from Developmental delay to Developmental disorder
Intellectual disability v3.1662 TAF4 Eleanor Williams commented on gene: TAF4: Not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 33875846 - Bertoli-Avella et al 2021 - identified two de novo LoF variants (splicing and nonsense) in two unrelated patients with dysmorphic features and one with intellectual disability and one with delayed speech and language development with global developmental delay.

PMID: 28191890 - Kosmicki et al 2017 - report a child with autism with an indel in TAF4 leading to a frameshift. No phenotypic details provided.

PMID: 27026076 - Langer et al 2016 - Taf4a−/− (gene encoding Taf4) mouse embryos survive until E9.5, but show severe growth retardation and specific defects in anterior and ventral patterning and morphogenesis.
Intellectual disability v3.1662 TAF4 Eleanor Williams Tag curated_removed was removed from gene: TAF4.
Intellectual disability v3.1662 TAF4 Eleanor Williams Entity copied from DDG2P v2.78
Intellectual disability v3.1662 TAF4 Eleanor Williams gene: TAF4 was added
gene: TAF4 was added to Intellectual disability. Sources: Expert Review Removed,Literature
curated_removed tags were added to gene: TAF4.
Mode of inheritance for gene: TAF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAF4 were set to 33875846
Phenotypes for gene: TAF4 were set to Developmental delay
Penetrance for gene: TAF4 were set to unknown
Intellectual disability v3.1661 RAP1GDS1 Eleanor Williams Tag Q3_22_rating tag was added to gene: RAP1GDS1.
Tag Q3_22_expert_review tag was added to gene: RAP1GDS1.
Intellectual disability v3.1661 RAP1GDS1 Eleanor Williams Classified gene: RAP1GDS1 as Amber List (moderate evidence)
Intellectual disability v3.1661 RAP1GDS1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber. There are now 4 families reported with the same splice site variant and a similar phenotype but intellectual disability is not seen in all probands. 2 of the families come from the same region. The ancestry of the other 2 families is not known. There is one additional case with a different 1bp deletion variant in RAP1GDS1 is also reported with ID as part of the phenotype. The expert reviewer proposes this gene should be green, and it also green on the PanelApp Australia Intellectual disability panel. Therefore the recommendation is for GREEN rating following GMS consideration and expert review.
Intellectual disability v3.1661 RAP1GDS1 Eleanor Williams Gene: rap1gds1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1660 RAP1GDS1 Eleanor Williams commented on gene: RAP1GDS1
Intellectual disability v3.1660 STT3A Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: STT3A.
Intellectual disability v3.1660 ALKBH8 Arina Puzriakova Publications for gene: ALKBH8 were set to 31130284; 31079898; 33544954; 34757492
Intellectual disability v3.1659 ALKBH8 Arina Puzriakova edited their review of gene: ALKBH8: Changed publications to: 31079898, 33544954, 34757492, 35571055; Changed phenotypes to: Intellectual developmental disorder, autosomal recessive 71, OMIM:618504
Intellectual disability v3.1659 ALKBH8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ALKBH8.
Intellectual disability v3.1659 ALKBH8 Arina Puzriakova reviewed gene: ALKBH8: Rating: GREEN; Mode of pathogenicity: None; Publications: Intellectual developmental disorder, autosomal recessive 71, OMIM:618504; Phenotypes: 31079898, 33544954, 34757492, 35571055; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1659 TFE3 Arina Puzriakova Phenotypes for gene: TFE3 were changed from TFE3-related intellectual disability with pigmentary mosaicism to Intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, OMIM:301066
Intellectual disability v3.1658 PIGP Arina Puzriakova Phenotypes for gene: PIGP were changed from Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to Developmental and epileptic encephalopathy 55, OMIM:617599
Intellectual disability v3.1657 KAT8 Arina Puzriakova Phenotypes for gene: KAT8 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism to Li-Ghorgani-Weisz-Hubshman syndrome, OMIM:618974; Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism
Intellectual disability v3.1656 TAF8 Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: TAF8.
Intellectual disability v3.1656 TAF8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TAF8.
Intellectual disability v3.1656 TAF8 Arina Puzriakova Classified gene: TAF8 as Amber List (moderate evidence)
Intellectual disability v3.1656 TAF8 Arina Puzriakova Added comment: Comment on list classification: New gene added by Jana Jezkova. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

TAF8 is associated with a relevant phenotype in OMIM (MIM# 619972) but is not yet listed in G2P.

8 individuals from 5 families have been reported in literature (PMIDs: 29648665; 35759269). Four families from different ethnic backgrounds harboured the same c.781-1G>A homozygous variant while sequencing in a sib pair revealed different compound het splice variants (c.45+4A>G and c.489G>A) in the TAF8 gene. Patients presented with an overlapping phenotype including microcephaly (8/8), DD and ID (8/8), spasticity (7/8), and seizures (6/8). Brain MRI have shown hypoplastic corpus callosum, hypomyelination, enlarged ventricles in most subjects, and additionally generalised brain atrophy in two sibs.
Intellectual disability v3.1656 TAF8 Arina Puzriakova Gene: taf8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1655 TAF8 Arina Puzriakova Publications for gene: TAF8 were set to PMID: 35759269
Intellectual disability v3.1654 TAF8 Arina Puzriakova Phenotypes for gene: TAF8 were changed from severe developmental delay; feeding problems; microcephaly; growth retardation; spasticity; epilepsy to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, OMIM:619972
Intellectual disability v3.1653 MED13L Arina Puzriakova Publications for gene: MED13L were set to 23403903
Intellectual disability v3.1652 MED13L Arina Puzriakova Phenotypes for gene: MED13L were changed from INTELLECTUAL DISABILITY to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789
Intellectual disability v3.1651 MAT1A Arina Puzriakova commented on gene: MAT1A: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Intellectual disability v3.1651 GJC2 Arina Puzriakova commented on gene: GJC2: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Intellectual disability v3.1650 SLC38A3 Catherine Snow Tag Q3_22_rating tag was added to gene: SLC38A3.
Intellectual disability v3.1650 SLC38A3 Catherine Snow Classified gene: SLC38A3 as Amber List (moderate evidence)
Intellectual disability v3.1650 SLC38A3 Catherine Snow Gene: slc38a3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1649 SLC38A3 Catherine Snow Phenotypes for gene: SLC38A3 were changed from Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia to Developmental and epileptic encephalopathy 102, 619881
Intellectual disability v3.1648 SLC38A3 Catherine Snow reviewed gene: SLC38A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 102, 619881; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1648 STT3A Tracy Lester reviewed gene: STT3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 34653363; Phenotypes: short stature, skeletal defects, intellectual disability, speech delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1648 CNNM2 Eleanor Williams Phenotypes for gene: CNNM2 were changed from Hypomagnesemia, seizures, and mental retardation 616418 to Hypomagnesemia, seizures, and mental retardation, OMIM:616418; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631
Intellectual disability v3.1647 ATP2B1 Catherine Snow Phenotypes for gene: ATP2B1 were changed from Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck to Intellectual developmental disorder, autosomal dominant 66, 619910
Intellectual disability v3.1646 ATP2B1 Catherine Snow Classified gene: ATP2B1 as Amber List (moderate evidence)
Intellectual disability v3.1646 ATP2B1 Catherine Snow Gene: atp2b1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1645 ATP2B1 Catherine Snow Tag Q3_22_rating tag was added to gene: ATP2B1.
Intellectual disability v3.1645 ATP2B1 Catherine Snow reviewed gene: ATP2B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1645 ADD1 Catherine Snow Classified gene: ADD1 as Amber List (moderate evidence)
Intellectual disability v3.1645 ADD1 Catherine Snow Gene: add1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1645 ADD1 Catherine Snow Classified gene: ADD1 as Amber List (moderate evidence)
Intellectual disability v3.1645 ADD1 Catherine Snow Gene: add1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1644 ADD1 Catherine Snow Tag Q3_22_rating tag was added to gene: ADD1.
Intellectual disability v3.1644 ADD1 Catherine Snow commented on gene: ADD1
Intellectual disability v3.1644 OGDHL Arina Puzriakova Tag Q3_22_rating tag was added to gene: OGDHL.
Intellectual disability v3.1644 OGDHL Arina Puzriakova Phenotypes for gene: OGDHL were changed from Neurodevelopmental disorder featuring epilepsy, hearing loss and visual impairment to Yoon-Bellen neurodevelopmental syndrome, OMIM:619701
Intellectual disability v3.1643 OGDHL Arina Puzriakova Classified gene: OGDHL as Amber List (moderate evidence)
Intellectual disability v3.1643 OGDHL Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote to Green at the next GMS panel update.

The NSRP1 gene is not yet associated with any phenotype in OMIM but has a 'moderate' disease confidence rating in G2P for 'OGDHL-related neurodevelopmental disorder with seizures, hearing loss and gait ataxia'.

At least 10 individuals from 9 unrelated families identified with biallelic variants in this gene (PMIDs: 28017472; 34800363). Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).
Intellectual disability v3.1643 OGDHL Arina Puzriakova Gene: ogdhl has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1642 OGDHL Arina Puzriakova Publications for gene: OGDHL were set to 34800363
Intellectual disability v3.1641 NSRP1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NSRP1.
Intellectual disability v3.1641 NSRP1 Arina Puzriakova Classified gene: NSRP1 as Amber List (moderate evidence)
Intellectual disability v3.1641 NSRP1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote to Green at the next GMS panel update.

The NSRP1 gene is not yet associated with any phenotype in OMIM but has a 'strong' disease confidence rating in G2P for 'NSRP1-associated developmental delay, epilepsy and microcephaly'.

Six individuals from three families with different homozygous LoF NSRP1 variants identified by Calame et al. 2021 (PMID: 34385670). Main clinical features include ID/DD (6/6), epilepsy (6/6, drug-resistant in 3/6), hypotonia (6/6), appendicular spasticity (6/6), microcephaly (5/6, Z-scores −0.95 to −5.60). Brain abnormalities included under-opercularization (3/4), simplified gyral pattern (3/4), superior and/or inferior cerebellar vermian hypoplasia (3/4), corpus callosum dysgenesis (1/4), and thin brainstem (1/4).
Intellectual disability v3.1641 NSRP1 Arina Puzriakova Gene: nsrp1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1640 NSRP1 Arina Puzriakova Phenotypes for gene: NSRP1 were changed from Epilepsy; Cerebral palsy; microcephaly; Intellectual disability to NSRP1-associated developmental delay, epilepsy and microcephaly
Intellectual disability v3.1639 HMGB1 Arina Puzriakova Classified gene: HMGB1 as Amber List (moderate evidence)
Intellectual disability v3.1639 HMGB1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update on ID and microcephaly gene panel based on >3 unrelated cases presenting with relevant phenotype due to heterozygous variant in the HMGB1 gene (PMID: 34164801)
Intellectual disability v3.1639 HMGB1 Arina Puzriakova Gene: hmgb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1638 HMGB1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: HMGB1.
Intellectual disability v3.1638 POLRMT Arina Puzriakova Entity copied from Mitochondrial disorders v2.112
Intellectual disability v3.1638 POLRMT Arina Puzriakova gene: POLRMT was added
gene: POLRMT was added to Intellectual disability. Sources: NHS GMS,Expert Review Amber
Q3_22_rating tags were added to gene: POLRMT.
Mode of inheritance for gene: POLRMT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: POLRMT were set to 24386581; 33602924
Phenotypes for gene: POLRMT were set to Combined oxidative phosphorylation deficiency 55, OMIM:619743
Intellectual disability v3.1637 GJB2 Arina Puzriakova commented on gene: GJB2
Intellectual disability v3.1636 GJB2 Arina Puzriakova Source Expert Review Red was added to GJB2.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Intellectual disability v3.1635 PRDM13 Ivone Leong Tag Q3_22_rating tag was added to gene: PRDM13.
Intellectual disability v3.1635 PRDM13 Ivone Leong edited their review of gene: PRDM13: Added comment: New publication. Publication reported eight individuals from four families of different origins with loss-of-function PRDM13 variants. Phenotypic findings included cerebellar hypoplasia and perinatal lethality associated with severe brainstem dysfunctions (e.g., feeding and respiratory difficulties, central apnea, bradycardia). Individuals were also reported to have severe global developmental delay. Therefore this gene should be rated Green.; Changed rating: GREEN; Changed publications to: 35390279
Intellectual disability v3.1635 PRDM13 Ivone Leong Entity copied from Disorders of sex development v2.65
Intellectual disability v3.1635 PRDM13 Ivone Leong gene: PRDM13 was added
gene: PRDM13 was added to Intellectual disability. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: PRDM13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM13 were set to 34730112
Phenotypes for gene: PRDM13 were set to congenital hypogonadotropic hypogonadism, MONDO:0015770; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, OMIM:619761
Intellectual disability v3.1634 BLOC1S1 Arina Puzriakova reviewed gene: BLOC1S1: Rating: ; Mode of pathogenicity: None; Publications: 33875846; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1634 ATG7 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.298
Intellectual disability v3.1634 ATG7 Arina Puzriakova gene: ATG7 was added
gene: ATG7 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: ATG7.
Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG7 were set to 34161705
Phenotypes for gene: ATG7 were set to Spinocerebellar ataxia, autosomal recessive 31, OMIM:619422
Intellectual disability v3.1633 TUBG1 Arina Puzriakova Publications for gene: TUBG1 were set to 29706637; 23603762; 29671837
Intellectual disability v3.1632 TAF8 Jana Jezkova changed review comment from: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8.
Sources: Literature; to: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8.
Sources: Literature
Intellectual disability v3.1632 TAF8 Jana Jezkova gene: TAF8 was added
gene: TAF8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF8 were set to PMID: 35759269
Phenotypes for gene: TAF8 were set to severe developmental delay; feeding problems; microcephaly; growth retardation; spasticity; epilepsy
Penetrance for gene: TAF8 were set to unknown
Review for gene: TAF8 was set to AMBER
Added comment: Eight patients reported in total. Six patients are homozygous for a recurrent NM_138572.2, c.781-1G>A variant. In two sibling patients, two novel compound heterozygous TAF8 splice site mutations, c.45+4A > G and c.489G>A were identified, which cause aberrant splicing as well as reduced expression and mislocalization of TAF8.
Sources: Literature
Intellectual disability v3.1632 STT3A Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic'. Congenital disorder of glycosylation due to monoallelic variants in STT3A has been identified in at least 16 patients from 9 families (PMID: 34653363). Phenotypes included mild-moderate ID/DD in 10/16 subjects.
Intellectual disability v3.1632 STT3A Arina Puzriakova Mode of inheritance for gene: STT3A was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1631 STT3A Arina Puzriakova Tag Q3_22_MOI tag was added to gene: STT3A.
Intellectual disability v3.1631 STT3A Arina Puzriakova Phenotypes for gene: STT3A were changed from Congenital disorder of glycosylation, type Iw, 615596 to Congenital disorder of glycosylation, type Iw, autosomal dominant, OMIM:619714; Congenital disorder of glycosylation, type Iw, autosomal recessive, OMIM:615596
Intellectual disability v3.1630 STT3A Arina Puzriakova Publications for gene: STT3A were set to 23842455; 28424003; 30701557
Intellectual disability v3.1629 EDEM3 Arina Puzriakova Entity copied from Congenital disorders of glycosylation v2.87
Intellectual disability v3.1629 EDEM3 Arina Puzriakova gene: EDEM3 was added
gene: EDEM3 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: EDEM3.
Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EDEM3 were set to 34143952
Phenotypes for gene: EDEM3 were set to Congenital disorder of glycosylation, type 2V, OMIM:619493
Intellectual disability v3.1628 PPFIBP1 Konstantinos Varvagiannis gene: PPFIBP1 was added
gene: PPFIBP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to 35830857; 30214071
Phenotypes for gene: PPFIBP1 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of brain morphology; Abnormality of the cerebral white matter; Cerebral calcification; Abnormal cortical gyration; Hypertonia; Spastic tetraplegia; Generalized hypotonia; Small for gestational age; Growth delay; Failure to thrive; Feeding difficulties; abnormal heart morphology; Hearing abnormality; Cryptorchidism; Abnormality of vision
Penetrance for gene: PPFIBP1 were set to Complete
Review for gene: PPFIBP1 was set to GREEN
Added comment: Consider inclusion with green rating in the ID, epilepsy as well as other likely relevant gene panels (microcephaly, white matter disorders, corpus callosum abnormalities, intracerebral calficication disorders, malformations of cortical development, hereditary spastic paraplegia, growth failure in early childhood, etc) based on the summary below.

----

Rosenhahn et al (2022 - PMID: 35830857) describe the phenotype of 16 individuals - belonging to 12 unrelated families - with biallelic PPFIBP1 pathogenic variants. Most (14/16) were born to consanguineous parents. One of these families was previously reported by Shaheen et al (2019 - PMID: 30214071) who first identified PPFIBP1 as a candidate gene for congenital microcephaly. In the current study, Rosenhahn also identified a fetus homozygous for a missense variant and similar features.

All individuals presented global DD/ID (16/16 - in 15 cases profound/severe) and epilepsy (16/16 - onset 1d-4y / median 2m - focal seizures in 11/16, epileptic spams in 7/16, generalized onset in 7/16, myoclonic in 6/16 - drug-resistant : 13/16). Almost all (15/16) had microcephaly, commonly congenital (9/16) and progressive (11/16). Other neurological findings included hypertonia (10/16), spastic tetraplegia (6/16), hypotonia (5/16), dystonic movements (3/16) or nystagmus (4/16). Brain abnormalities were identified in all investigated with MRI and included leukoencephalopathy (11/14) mostly periventricular, abnormal cortex morphology (7/14 - polymicrogyria 1, increased cortical thickness 4, pachygyria 3), cortical atrophy, corpus callosum hypoplasia (7/14). Intracranial calcifications were identified in all (9/9) investigated with CT scan. Abnormal growth was reported for several (SGA in 9/16, FTT 8/16, short stature 7/16) often associated with feeding difficulties (7/16). Other features incl. abnormal hearing (4/16), congenital heart defects (7/16), ophthalmologic findings (8/16), undescended testes (3/10). There were no overlapping facial features.

The fetus displayed similar features incl. SGA, microcephaly, intracranial calcifications.

Investigations incl. exome/genome sequencing (singleton or trio) with Sanger for confirmation/segregation of variants where necessary. Variable previous investigations incl. metabolic screening, TORCH screening, chromosomal studies (CMA) are mentioned in the supplement and were non-diagnostic. Additional candidate variants were identified in few cases although cases with plausible dual diagnoses (e.g. ind14) were not included in the overall phenotypic description.

9 pLoF variants (nonsense, frameshift, 1 splicing) predicted to lead to NMD were identified. There were no functional studies performed.
The missense variant c.2177G>T / p.Gly726Val (NM_003622.4) was predicted deleterious by in silico tools while the AA change causing severe steric problems upon modelling.

PPFIBP1 encodes PPFIA-binding protein 1 also known as liprin-β1. As the authors discuss: The liprin family of proteins comprises liprins α1 to 4 and liprin β1 and β2 in mammals. Liprin β1 is known to homodimerize and heterodimerize with α-liprins. In fibroblast cultures liprins β1 and α1 colocalize to cell membrane and periphery of focal adhesions. Members of the liprin-α fam. are scaffold proteins playing a role in synapse formation/signaling and axonal transport.

A ko model of the PPFIBP1 ortholog in C.elegans displayed abnormal locomotion behavior. In Drosophila, null-allele mutants resulted in altered axon outgrowth and synapse formation of R7 photoreceptors and reduced neuromuscular junction size (Refs provided in article).

Using a PPFIBP1/hlb-1 ko C.elegans model the authors demonstrated defects in spontaneous and light-induced behavior. Sensitivity of the worms to an acetylcholinesterase inhibitor (aldicarb) was suggestive of a presynaptic defect.

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There is currently no PPFIBP1 - associated phenotype in OMIM / G2P.
SysNDD lists PPFIBP1 among the ID genes (limited evidence based on the 3 sibs reported by Shaheen et al, 2019 - PMID: 30214071).
In PanelApp Australia the gene is listed with green rating for ID, epilepsy, microcephaly based on the medRxiv pre-print.
Sources: Literature
Intellectual disability v3.1628 SEMA3E Sarah Leigh gene: SEMA3E was added
gene: SEMA3E was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SEMA3E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SEMA3E were set to 35628442
Phenotypes for gene: SEMA3E were set to Severe Intellectual Disability with Cognitive Regression
Review for gene: SEMA3E was set to AMBER
Added comment: Not associated with a phenotype in OMIM or Gen2Phen. One variant has been reported in a case of Severe Intellectual Disability with Cognitive Regression (PMID: 35628442). PMID: 35628442 also describes functional studies which show that this variant impairs protein secretion and hampers the binding to both embryonic mouse neuronal cells and tissues, furthermore, SEMA3E was revealed to be expressed during human brain development.
Sources: Literature
Intellectual disability v3.1627 EMC1 Dmitrijs Rots reviewed gene: EMC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35234901; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1627 SLC1A2 Sarah Leigh Phenotypes for gene: SLC1A2 were changed from Epileptic encephalopathy, early infantile, 41, 617105; Intellectual disability to Epileptic encephalopathy, early infantile, 41, OMIM:617105; developmental and epileptic encephalopathy, 41, MONDO:0014916
Intellectual disability v3.1626 HECW2 Arina Puzriakova Publications for gene: HECW2 were set to 25529582
Intellectual disability v3.1625 MAL Sarah Leigh reviewed gene: MAL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1625 MAL Sarah Leigh Classified gene: MAL as Amber List (moderate evidence)
Intellectual disability v3.1625 MAL Sarah Leigh Gene: mal has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1624 MAL Julia Baptista gene: MAL was added
gene: MAL was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to developmental delay; nystagmus; progressive motor deterioration; dysmyelination
Review for gene: MAL was set to AMBER
Added comment: Single consanguineous family reported with two affected children (DD and nystagmus). New onset ataxia and cerebellar volume loss with patchy dysmyelination. Homozygous missense variant identified by exome analysis segregated with the condition. Functional data suggested that p.(Ala109Asp) severely affects protein folding of MAL, leading to mislocalization in the ER.
Sources: Literature
Intellectual disability v3.1624 GNB2 Arina Puzriakova Phenotypes for gene: GNB2 were changed from Intellectual disability to Neurodevelopmental disorder with hypotonia and dysmorphic facies, OMIM:619503
Intellectual disability v3.1623 MTM1 Arina Puzriakova Phenotypes for gene: MTM1 were changed from X-linked Myotubular Myopathy; MYOTUBULAR MYOPATHY, X-LINKED to Myopathy, centronuclear, X-linked, OMIM:310400
Intellectual disability v3.1622 WNK3 Arina Puzriakova Mode of inheritance for gene: WNK3 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1621 WNK3 Arina Puzriakova Publications for gene: WNK3 were set to 26350204
Intellectual disability v3.1620 WNK3 Arina Puzriakova Phenotypes for gene: WNK3 were changed from X_linked intellectual disability; XLID to X-linked intellectual disability, MONDO:0100284
Intellectual disability v3.1619 WNK3 Arina Puzriakova Classified gene: WNK3 as Amber List (moderate evidence)
Intellectual disability v3.1619 WNK3 Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to promote this gene to Green at the next GMS review - at least 14 individuals from 6 unrelated families, all presenting with ID in association with variants in the WNK3 gene.
Intellectual disability v3.1619 WNK3 Arina Puzriakova Gene: wnk3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1618 WNK3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: WNK3.
Intellectual disability v3.1618 WNK3 Arina Puzriakova reviewed gene: WNK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 35678782; Phenotypes: Intellectual disability, MONDO:0001071; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1618 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Intellectual disability v3.1618 KIAA1109 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; to: Added new-gene-name tag, new approved HGNC gene symbol for KIAA1109 is BLTP1.
Intellectual disability v3.1618 SKIV2L Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.; to: Added new-gene-name tag, new approved HGNC gene symbol for SKIV2L is SKIC2.
Intellectual disability v3.1618 TTC37 Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for TTC37 is SKIC3.; to: Added new-gene-name tag, new approved HGNC gene symbol for TTC37 is SKIC3.
Intellectual disability v3.1618 TTC37 Sarah Leigh Tag new-gene-name tag was added to gene: TTC37.
Intellectual disability v3.1618 TTC37 Sarah Leigh commented on gene: TTC37
Intellectual disability v3.1618 SKIV2L Sarah Leigh Tag new-gene-name tag was added to gene: SKIV2L.
Intellectual disability v3.1618 SKIV2L Sarah Leigh commented on gene: SKIV2L: The new_gene_name tag has been added. The new name for SKIV2L is SKIC2.
Intellectual disability v3.1618 KIAA1109 Sarah Leigh Tag new-gene-name tag was added to gene: KIAA1109.
Intellectual disability v3.1618 KIAA1109 Sarah Leigh edited their review of gene: KIAA1109: Added comment: The new_gene_name tag has been added. The new name for KIAA1109 is BLTP1.; Changed phenotypes to: Alkuraya-Kucinskas syndrome 617822
Intellectual disability v3.1618 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Intellectual disability v3.1618 GBA Sarah Leigh commented on gene: GBA
Intellectual disability v3.1618 PCDHGC4 Sarah Leigh Phenotypes for gene: PCDHGC4 were changed from Neurodevelopmental abnormality HP:0012759 to Neurodevelopmental disorder with poor growth and skeletal anomalies, OMIM:619880
Intellectual disability v3.1617 PCDHGC4 Sarah Leigh Tag gene-checked was removed from gene: PCDHGC4.
Intellectual disability v3.1617 CHD5 Sarah Leigh Phenotypes for gene: CHD5 were changed from OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Parenti-Mignot neurodevelopmental syndrome, OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1616 CHD5 Sarah Leigh Phenotypes for gene: CHD5 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to OMIM:610771; Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1615 CHD5 Sarah Leigh Tag gene-checked was removed from gene: CHD5.
Intellectual disability v3.1615 NR4A2 Sarah Leigh Phenotypes for gene: NR4A2 were changed from Language impairment; Intellectual disability; Autism; Behavioral abnormality; No OMIM number to Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, OMIM:619911
Intellectual disability v3.1614 NR4A2 Sarah Leigh Tag gene-checked was removed from gene: NR4A2.
Intellectual disability v3.1614 GNAI1 Sarah Leigh Tag gene-checked was removed from gene: GNAI1.
Intellectual disability v3.1614 ZNF526 Sarah Leigh Tag gene-checked was removed from gene: ZNF526.
Intellectual disability v3.1614 ATP6V0A1 Sarah Leigh Added comment: Comment on phenotypes: Phenotype from Gen2Phen https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4422
Intellectual disability v3.1614 ATP6V0A1 Sarah Leigh Phenotypes for gene: ATP6V0A1 were changed from ATP6V0A1-related developmental disorder (monoallelic) to ATP6V0A1-related developmental disorder (monoallelic)
Intellectual disability v3.1613 ATP6V0A1 Sarah Leigh Phenotypes for gene: ATP6V0A1 were changed from Developmental disorder; Rett syndrome-like to ATP6V0A1-related developmental disorder (monoallelic)
Intellectual disability v3.1612 ATP6V0A1 Sarah Leigh Tag Q3_22_MOI tag was added to gene: ATP6V0A1.
Intellectual disability v3.1612 ATP6V0A1 Sarah Leigh edited their review of gene: ATP6V0A1: Added comment: Not associated with a phenotype in OMIM, but as definitive Gen2Phen gene for ATP6V0A1-related developmental disorder (monoallelic). At least four variants have been reported as de novo heterozygous variants in 14 apparently unrelated cases, with intellectual disability (11/11 cases who could be assessed), epilepsy/EEG abnormalities (11/13 who could be assessed), microcephaly (6/12 cases who could be assessed), ataxia (6/13 cases who could be assessed) and various other phenotypic features (PMID: 34909687 (table 1) & 33833240). Six additional ATP6V0A1 variants were reported as biallelic in four apparently unrelated cases, who all had intellectual disability, epilepsy/EEG abnormalities plus cerebral and cerebellar atrophy / brain atrophy (PMID: 34909687 (table 1) & 33833240).; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1612 ATP6V0A1 Sarah Leigh changed review comment from: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line Gen2Phen and the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.; to: Comment on mode of inheritance: Monoallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line Gen2Phen and the views Zornitza Stark and Mike Spiller who have reviewed this gene.
Intellectual disability v3.1612 ATP6V0A1 Sarah Leigh Publications for gene: ATP6V0A1 were set to 30842224; 33057194; 34909687
Intellectual disability v3.1611 ATP6V0A1 Sarah Leigh changed review comment from: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.; to: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line Gen2Phen and the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.
Intellectual disability v3.1611 ATP6V0A1 Sarah Leigh Added comment: Comment on mode of inheritance: Monallelic mode of inheritance has been selected for ATP6V0A1, although four families showed biallelic ATP6V0A1 variants. This in line the views Zornitza Stark and Mike Spiller who have reviewed this gene, and reflects the inconstitancies of the phenotypes amongst these individuals. As more data is obtained, it maybe that the mode of inheritance is changed to both mono and biallelic.
Intellectual disability v3.1611 ATP6V0A1 Sarah Leigh Mode of inheritance for gene: ATP6V0A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1610 ATP6V0A1 Sarah Leigh Classified gene: ATP6V0A1 as Amber List (moderate evidence)
Intellectual disability v3.1610 ATP6V0A1 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 v3.1610 ATP6V0A1 Sarah Leigh Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1609 ATP6V0A1 Sarah Leigh Tag Q3_22_rating tag was added to gene: ATP6V0A1.
Tag Q3_22_NHS_review tag was added to gene: ATP6V0A1.
Intellectual disability v3.1609 ATP6V0A1 Sarah Leigh Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Intellectual disability v3.1608 TMEM63C Sarah Leigh Classified gene: TMEM63C as Amber List (moderate evidence)
Intellectual disability v3.1608 TMEM63C Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review, as mild intellectual disability has been diagnosed in the three families carrying TMEM63C variants reported in PMID: 35718349.
Intellectual disability v3.1608 TMEM63C Sarah Leigh Gene: tmem63c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1607 TMEM63C Sarah Leigh gene: TMEM63C was added
gene: TMEM63C was added to Intellectual disability. Sources: Literature
Q3_22_rating tags were added to gene: TMEM63C.
Mode of inheritance for gene: TMEM63C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM63C were set to 35718349
Phenotypes for gene: TMEM63C were set to hereditary spastic paraplegia, MONDO:0019064
Review for gene: TMEM63C was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID:35718349 reports four TMEM63C variants in seven individuals from three unrelated families with childhood onset hereditary spastic paraplegia, with mild intellectual disability in some cases. Functional studies in PMID:35718349, reveal a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies.
Sources: Literature
Intellectual disability v3.1606 ATP6V0A1 Mike Spiller changed review comment from: Bott et al 2021 PMID: 34909687

17 individuals from 14 unrelated families

12 individuals with de novo variants in ATP6V0A1.
Associated with severe intellectual disability and refractory seizures following initial normal development.
1 stillborn; other 11 all have intellectual disability and slowing of developmental progression. 10 have epilepsy, microcephaly also common and MRI abnormalities in some.
Dysmorphic features less common.

7/12 have recurrent hotspot variant NM_001130021.3 c.2219G>A R740Q.

Biallelic inheritance also suggested - 2 separate families (apparently unrelated by IBD analysis) with affected individuals compound heterozygous for c.445delG p.(Glu149fs) and c.1483C>T p.(Arg495Trp).
Phenotype of ID, epilepsy, but with ataxia and cerebellar anomalies.

Gene involved in proton transport into organelles. Cell lines stably expressing R740Q show reduced endolysosome acidification consistent with reduced transporter function.
Supported by data showing impaired maturation of Cathepsin D (requires acidic pH).
Also refer to studies of yeast homologue showing that R735 (corresponds to human R740) is essential for proton transport function (Kawasaki-Nishi et al 2001 PMID: 11592980).

Strong evidence that pathogenic missense variants in this gene cause severe ID/epilepsy, Less certain for biallelic inheritance.
Recommend upgrade to Green for ID and epilepsy.; to: Bott et al 2021 PMID: 34909687

17 individuals from 14 unrelated families

12 individuals with de novo variants in ATP6V0A1.
Associated with severe intellectual disability and refractory seizures following initial normal development.
1 stillborn; other 11 all have intellectual disability and slowing of developmental progression. 10 have epilepsy, microcephaly also common and MRI abnormalities in some.
Dysmorphic features less common.

7/12 have recurrent hotspot variant NM_001130021.3 c.2219G>A R740Q.

Biallelic inheritance also suggested - 2 separate families (apparently unrelated by IBD analysis) with affected individuals compound heterozygous for c.445delG p.(Glu149fs) and c.1483C>T p.(Arg495Trp).
Phenotype of ID, epilepsy, but with ataxia and cerebellar anomalies.

Gene involved in proton transport into organelles. Cell lines stably expressing R740Q show reduced endolysosome acidification consistent with reduced transporter function.
Supported by data showing impaired maturation of Cathepsin D (requires acidic pH).
Also refer to studies of yeast homologue showing that R735 (corresponds to human R740) is essential for proton transport function (Kawasaki-Nishi et al 2001 PMID: 11592980).

Strong evidence that heterozygous pathogenic missense variants in this gene cause severe ID/epilepsy, Less certain for biallelic inheritance.
Recommend upgrade to Green for ID and epilepsy.
Intellectual disability v3.1606 ATP6V0A1 Mike Spiller reviewed gene: ATP6V0A1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 34909687; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1606 HIST1H4J Arina Puzriakova Tag watchlist tag was added to gene: HIST1H4J.
Intellectual disability v3.1606 HIST1H4J Arina Puzriakova Phenotypes for gene: HIST1H4J were changed from microcephaly; intellectual disability; dysmorphic features to ?Tessadori-van Haaften neurodevelopmental syndrome 2 , OMIM:619759
Intellectual disability v3.1605 HIST1H4J Arina Puzriakova Publications for gene: HIST1H4J were set to 31804630; 35202563
Intellectual disability v3.1605 HIST1H4J Arina Puzriakova Publications for gene: HIST1H4J were set to 31804630
Intellectual disability v3.1604 SYNE2 Sarah Leigh gene: SYNE2 was added
gene: SYNE2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SYNE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SYNE2 were set to 34573277
Phenotypes for gene: SYNE2 were set to autism spectrum disorder, developmental delay and intellectual disability
Review for gene: SYNE2 was set to RED
Added comment: Biallelic SYNE2 variants are not associated with autism spectrum disorder, developmental delay and intellectual disability in OMIM or Gen2Phen. PMID: 34573277 reports compound heterozygous SYNE2 variants in a child with autism spectrum disorder, developmental delay and intellectual disability, together with supportive functional studies.
Sources: Literature
Intellectual disability v3.1603 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from Brugada syndrome 3 611875; Timothy syndrome 601005 to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder
Intellectual disability v3.1602 ALKBH8 Sarah Leigh Publications for gene: ALKBH8 were set to 31130284; 31079898
Intellectual disability v3.1601 ZMYM2 Sarah Leigh Phenotypes for gene: ZMYM2 were changed from Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, OMIM:619522
Intellectual disability v3.1600 ZMYM2 Sarah Leigh Tag Q3_22_rating tag was added to gene: ZMYM2.
Tag Q3_22_NHS_review tag was added to gene: ZMYM2.
Intellectual disability v3.1600 ZMYM2 Sarah Leigh edited their review of gene: ZMYM2: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for ZMYM2-related developmental disorder (monoallelic). At least 3 variants have been reported in cases with mild to unclassified intellectual disability in PMID: 32891193. The review from Tracy Lester (Genetics laboratory, Oxford UK) mentions several additional de novo variants reported by Decipher associated with intellectual / developmental disability.; Changed rating: GREEN
Intellectual disability v3.1600 ZMYM2 Sarah Leigh Classified gene: ZMYM2 as Amber List (moderate evidence)
Intellectual disability v3.1600 ZMYM2 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 v3.1600 ZMYM2 Sarah Leigh Gene: zmym2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1599 CUL3 Sarah Leigh Tag Q3_22_rating tag was added to gene: CUL3.
Tag Q3_22_NHS_review tag was added to gene: CUL3.
Intellectual disability v3.1599 CUL3 Sarah Leigh edited their review of gene: CUL3: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least seven variants have been reported in publications (PMIDs: 32341456;25969726;31696658;33097317;30311385) in at least seven unrelated cases, together with a case reported by Julie Evans (South West Genomic Laboratory Hub) all being diagnosed with Neurodevelopmental disorder with or without autism or seizures, OMIM:619239. Severe intellectual disability (ID) was observed in two of these cases, mild in three cases and unclassified ID in another case. Seizures were also evident in three cases and a febrile seizure was reported in another case.; Changed rating: GREEN
Intellectual disability v3.1599 CUL3 Sarah Leigh Classified gene: CUL3 as Amber List (moderate evidence)
Intellectual disability v3.1599 CUL3 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 v3.1599 CUL3 Sarah Leigh Gene: cul3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1598 CUL3 Sarah Leigh Publications for gene: CUL3 were set to 32341456; 25969726; 31696658; 33097317
Intellectual disability v3.1597 CUL3 Sarah Leigh Phenotypes for gene: CUL3 were changed from Global developmental delay; Intellectual disability; Autism Spectrum Disorder; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE, 614496 to Neurodevelopmental disorder with or without autism or seizures, OMIM:619239
Intellectual disability v3.1596 CUL3 Sarah Leigh Publications for gene: CUL3 were set to 32341456; 25969726
Intellectual disability v3.1595 CLIC2 Sarah Leigh Publications for gene: CLIC2 were set to 22814392; 25927380
Intellectual disability v3.1594 GLS_GCA Eleanor Williams Tag for-review was removed from STR: GLS_GCA.
Intellectual disability v3.1594 RYR2 Sarah Leigh changed review comment from: PMID: 30170228 reports 34/421 RYR2-associated catecholaminergic polymorphic ventricular tachycardia (CPVT1) patients had intellectual disability. It was also possible to establish that de novo variants had arisen in 13/24 of these cases. RYR2 has not been made green on this panel at present, as ID is not a common feature of CPVT1 and it would appear that penetrance is incomplete.; to: PMID: 30170228 reports 34/421 RYR2-associated catecholaminergic polymorphic ventricular tachycardia (CPVT1) patients had intellectual disability. It was also possible to establish that de novo RYR2 variants had arisen in 13/24 of these cases. RYR2 has not been made green on this panel at present, as ID is not a common feature of CPVT1 and it would appear that penetrance is incomplete.
Intellectual disability v3.1594 RYR2 Sarah Leigh reviewed gene: RYR2: Rating: ; Mode of pathogenicity: None; Publications: 30170228; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1594 RYR2 Sarah Leigh Classified gene: RYR2 as Amber List (moderate evidence)
Intellectual disability v3.1594 RYR2 Sarah Leigh Gene: ryr2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1593 RYR2 Sarah Leigh Tag Q3_22_rating was removed from gene: RYR2.
Tag Q3_22_expert_review was removed from gene: RYR2.
Intellectual disability v3.1593 RYR2 Sarah Leigh Tag Q3_22_rating tag was added to gene: RYR2.
Tag Q3_22_expert_review tag was added to gene: RYR2.
Intellectual disability v3.1593 ZMYM2 Tracy Lester reviewed gene: ZMYM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32891193; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1593 RYR2 Dmitrijs Rots gene: RYR2 was added
gene: RYR2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RYR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RYR2 were set to 30170228
Penetrance for gene: RYR2 were set to Incomplete
Review for gene: RYR2 was set to GREEN
Added comment: In a large cohort of RYR2-related CPVT, 8% of individuals (34 of 421) were having ID of various severity. Funcional data suggest that highly damaging RYR2 variants underlie ID.
Sources: Literature
Intellectual disability v3.1593 ALKBH8 Konstantinos Varvagiannis edited their review of gene: ALKBH8: Changed publications to: 31079898, 33544954, 34757492
Intellectual disability v3.1593 ALKBH8 Konstantinos Varvagiannis edited their review of gene: ALKBH8: Added comment: Please consider upgrade to green rating.

2 additional relevant families reported in literature, as summarized below. While affected individuals from 3 (of the 4 total) families with the disorder were homozygous for truncating variants in the last exon (potentially corresponding to hypomorphic / incomplete LoF rather than null alleles), a more recent publication describes 2 sibs homozygous for a missense SNV with demonstrated loss-of-function in the context of normal protein levels.

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Saad et al (2020 - PMID: 33544954) report 2 sibs, born to consanguineous parents from Egypt homozygous for an ALKBH8 frameshift variant. Both exhibited global DD and ID (proband IQ of 51 / Stanford Binet test, sib: 42 using Weschler scale). There was no history of seizures. Family based exome sequencing of both sibs and parents revealed homozygosity for NM_001301010.1:c.1684delC [p.(Arg562Alafs*56))] within a region of AOH. As the authors note this variant also occurred in the last exon of the gene, likely escaping NMD and based on previous evidence from Monnies et al, hypothesize that truncating variants in the last exon represent hypomorphic alleles encoding for a partially functional protein, while protein truncating variants in earlier exons may be null alleles.

Maddirevula et al (2021 - PMID: 34757492) describe the phenotype of 2 sibs, homozygous for a missense variant. Features included severe DD and ID, microcephaly, facial dysmorphism and epilepsy (the latter limited to the elder one). Exome with autozygome analysis identified homozygosity for a missense variant (NM_138775.2:c.1874G>A / p.Arg625His) with Sanger for confirmation / segregation studies.LC-MS/MS using tRNA isolated from LCLs from the affected individual, a carrier parent and controls revealed complete loss of ALKBH8-dependent tRNA posttranscriptional modifications, the results being suggestive of abrogation of the catalytic activities of both MT and Ox domains. The protein was detected at low levels in LCLs from control and patient samples, a finding that was also supported by immunoblot analysis suggesting that the observed loss-of-function is not mediated by loss of the protein.; Changed rating: GREEN; Changed publications to: 33544954, 34757492
Intellectual disability v3.1593 CUL3 Julie Evans reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, seizures, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1593 ACO2 Sarah Leigh Tag Q2_22_MOI tag was added to gene: ACO2.
Intellectual disability v3.1593 ACO2 Sarah Leigh commented on gene: ACO2: New paper (34056600) describing ACO2 as a cause of autosomal dominant optic atrophy - update of inheritance needed.
Tom Cullup (Great Ormond Street Hospital), 17 Feb 2022
Intellectual disability v3.1593 ACO2 Sarah Leigh reviewed gene: ACO2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1593 ACO2 Sarah Leigh Publications for gene: ACO2 were set to 22405087; 25351951
Intellectual disability v3.1592 PHF14 Sarah Leigh Tag Q2_22_rating tag was added to gene: PHF14.
Intellectual disability v3.1592 PHF14 Sarah Leigh reviewed gene: PHF14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1592 PHF14 Sarah Leigh Publications for gene: PHF14 were set to 35074918
Intellectual disability v3.1591 PHF14 Sarah Leigh Classified gene: PHF14 as Amber List (moderate evidence)
Intellectual disability v3.1591 PHF14 Sarah Leigh Gene: phf14 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1590 MED13 Catherine Snow Tag Q2_22_rating tag was added to gene: MED13.
Tag Q2_22_NHS_review tag was added to gene: MED13.
Intellectual disability v3.1590 MED13 Catherine Snow reviewed gene: MED13: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33931951; Phenotypes: Intellectual developmental disorder, autosomal dominant 61 OMIM:618009; Mode of inheritance: None
Intellectual disability v3.1590 SRRM2 Sarah Leigh edited their review of gene: SRRM2: Added comment: Not associated with a phenotype in OMIM and as definitive Gen2Phen gene for SRRM2-related developmental disorder (monoallelic). At least 22 loss of function SRRM2 variants have been reported in PMID: 35567594 in unrelated cases of which 16/20 exhibit variable mild intellectual disability.; Changed rating: GREEN
Intellectual disability v3.1590 SRRM2 Sarah Leigh Tag Q2_22_rating tag was added to gene: SRRM2.
Intellectual disability v3.1590 SRRM2 Sarah Leigh Classified gene: SRRM2 as Amber List (moderate evidence)
Intellectual disability v3.1590 SRRM2 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 v3.1590 SRRM2 Sarah Leigh Gene: srrm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1589 SRRM2 Sarah Leigh changed review comment from: Comment on phenotypes: SRRM2-related developmental disorder (monoallelic) is the phenotype listed by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4427) to be associated with SRRM2 variants.; to: Comment on phenotypes: SRRM2-related developmental disorder (monoallelic) is the phenotype listed by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4427) to have a definitive association with SRRM2 variants.
Intellectual disability v3.1589 SRRM2 Sarah Leigh Added comment: Comment on phenotypes: SRRM2-related developmental disorder (monoallelic) is the phenotype listed by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4427) to be associated with SRRM2 variants.
Intellectual disability v3.1589 SRRM2 Sarah Leigh Phenotypes for gene: SRRM2 were changed from Developmental disorders to SRRM2-related developmental disorder (monoallelic)
Intellectual disability v3.1588 SRRM2 Sarah Leigh Publications for gene: SRRM2 were set to 33057194
Intellectual disability v3.1587 PRPF8 Sarah Leigh edited their review of gene: PRPF8: Added comment: Associated with Retinitis pigmentosa 13 (OMIM:600059) in OMIM, but not with PRPF8-related developmental disorder (monoallelic) and as a both RD and IF Gen2Phen gene for PRPF8-related developmental disorder (monoallelic). PMID: 35543142 reports 14 PRPF8 variants in unrelated cases (12/14 variants were confirmed as de novo). Intellectual disability was observed in 13/14 of these cases and seizures were evident in 4/14 cases.; Changed rating: GREEN
Intellectual disability v3.1587 PRPF8 Sarah Leigh Added comment: Comment on phenotypes: Gen2Phen phenotype: PRPF8-related developmental disorder (monoallelic) in addition to Retinitis pigmentosa 13
Intellectual disability v3.1587 PRPF8 Sarah Leigh Phenotypes for gene: PRPF8 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, OMIM:600059 to PRPF8-related developmental disorder (monoallelic); Retinitis pigmentosa 13, OMIM:600059
Intellectual disability v3.1586 PRPF8 Sarah Leigh Classified gene: PRPF8 as Amber List (moderate evidence)
Intellectual disability v3.1586 PRPF8 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 v3.1586 PRPF8 Sarah Leigh Gene: prpf8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1585 PRPF8 Sarah Leigh Tag Q2_22_rating tag was added to gene: PRPF8.
Intellectual disability v3.1585 PRPF8 Sarah Leigh Phenotypes for gene: PRPF8 were changed from Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, MIM # 600059 to Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, OMIM:600059
Intellectual disability v3.1584 PRPF8 Sarah Leigh Publications for gene: PRPF8 were set to 35543142
Intellectual disability v3.1583 DROSHA Sarah Leigh reviewed gene: DROSHA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1583 DROSHA Sarah Leigh Classified gene: DROSHA as Amber List (moderate evidence)
Intellectual disability v3.1583 DROSHA Sarah Leigh Gene: drosha has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1582 DROSHA Sarah Leigh Tag locus-type-rna-micro tag was added to gene: DROSHA.
Tag Q2_22_rating tag was added to gene: DROSHA.
Intellectual disability v3.1582 SNORD118 Sarah Leigh edited their review of gene: SNORD118: Added comment: In response to Ian Berry's (Leeds Genetics Laboratory) review, SNORD118 should be promoted to green on this panel.; Changed rating: GREEN
Intellectual disability v3.1582 SNORD118 Sarah Leigh Tag Q2_22_rating tag was added to gene: SNORD118.
Tag Q2_22_NHS_review tag was added to gene: SNORD118.
Intellectual disability v3.1582 SNORD118 Sarah Leigh Classified gene: SNORD118 as Amber List (moderate evidence)
Intellectual disability v3.1582 SNORD118 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 v3.1582 SNORD118 Sarah Leigh Gene: snord118 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1581 SCAF4 Sarah Leigh edited their review of gene: SCAF4: Added comment: In repsonse to Ian Berry's (Leeds Genetics Laboratory) review, which also reports an additional patient with a de novo truncating variant, there is sufficient evidence for SCAF4 to be green on this panel.; Changed rating: GREEN
Intellectual disability v3.1581 SCAF4 Sarah Leigh Tag watchlist was removed from gene: SCAF4.
Tag Q2_22_rating tag was added to gene: SCAF4.
Tag Q2_22_NHS_review tag was added to gene: SCAF4.
Intellectual disability v3.1581 SCAF4 Sarah Leigh Classified gene: SCAF4 as Amber List (moderate evidence)
Intellectual disability v3.1581 SCAF4 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 v3.1581 SCAF4 Sarah Leigh Gene: scaf4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1580 SNORD118 Ian Berry reviewed gene: SNORD118: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.1580 SRRM2 Konstantinos Varvagiannis changed review comment from: Recent report of 22 unrelated individuals with nonsense / frameshift variants or microdeletions of SRRM2 reported. DD was a universal feature, with ID present in some (16/20 - in all cases mild). Note possible 'overlap' with the study by Kaplanis et al / DDD study cited in the previous review by Prof. Z. Stark.

The gene is not intolerant to missense variation (z-score of -6.28) and eventual contribution of missense variants is not known. While SRRM2 is known to encode a splicing factor promoting interaction between mRNA and the spliceosome catalytic machinery (discussed below) molecular and functional studies are required to characterize the pathogenesis of the disorder.

There is currently no SRRM2-related phenotype in OMIM. SRRM2 is included in the DD panel of G2P [confidence : definitive, SRRM2-related developmental disorder (monoallelic), cited : Kaplanis et al / DDD]. In PanelApp Australia SRRM2 has amber rating in the ID panel (based on the study by Kaplanis et al / DDD).

Consider inclusion with green rating (several individuals/families/variants - rather consistent phenotype) or amber rating (as for pathogenesis / also DD universal feature, ID observed in most but not all affected individuals, when present always mild).

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Cuinat et al. (2022 - PMID: 35567594) report on 22 individuals with LoF variants in SRRM2.

All subjects had DD (22/22) predominantly affecting language acquisition (16/19) while motor delay was less common. ID was present in 16/20 (in all cases mild) of the individuals with available neurocognitive evaluation. Some individuals displayed autistic features (9/22) although others had a friendly - in some cases excessively - sociable personality (8/22). Other features included hypotonia in some, growth abnormalities (12/22 overweight, 7/22 with obesity, 4/22 tall stature). Morphological features incl. facial (20/22 - e.g. deep-set eyes, bulbous nasal tip or smooth philtrum) or small hands and feet (6/22) were also reported. Visceral / skeletal abnormalities were uncommon.

SRRM2 encodes serine/arginine repetitive matrix protein 2 (or SRm300), a nuclear ubiquitous protein forming a complex with the protein encoded by SRRM1 (SRm160). As the authors summarize this complex is one of the main catalytic components of the spliceosome having a role in pre-mRNA maturation.

12 subjects harbored frameshift variants, 8 nonsense while 2 further ones had microdeletions (66-270kb) spanning - but not limited to - SRRM2 (other genes not predicted to be haploinsufficient). The gene has a pLI in gnomAD of 1 (o/e = 0.06) while it appears to be tolerant to missense variation (z-score of -6.28 / o/e = 1.43). With the exception of the 2 subjects harboring a microdeletion, all were investigated with singleton/trio ES with no other candidate variants.

Variants occurred de novo in 19/22. Mosaicism (in an asymptomatic parent) was suspected based on the reads in one case. One individual had inherited the variant (parent with DD). Segregation analyses was not possible in one case.

While one variant lied in ex2 (of 15) all others were in the large ex11 (encoding ~2000 of the 2752 total residues based on the schema provided / NM_016333.4), all predicted to lead to NMD.

There are no studies for pathogenesis of the disorder or the underlying effect of variants. Animal models not discussed.

The authors do a comparison with other 'spliceosomopathies', e.g. due to variants in SF3B4 or EFTUD2, where DD/ID can be a feature although these disorders have also prominent skeletal features.

Previously, as the authors note, the study by Kaplanis et al (2020 - PMID: 33057194) integrating exome sequence data from ~31,000 parent-offspring trios of individuals with developmental disorders had identified SRRM2 among 28 genes significantly enriched in LoF variants. [ The present study possibly includes individuals from the aforementioned cohort, e.g. from Radboudumc ].; to: Recent report of 22 unrelated individuals with nonsense / frameshift variants or microdeletions of SRRM2. DD was a universal feature, with ID present in some affected individuals (16/20 - in all cases mild). Note possible 'overlap' with the study by Kaplanis et al / DDD study cited in the previous review by Prof. Z. Stark.

The gene is not intolerant to missense variation (z-score of -6.28) and eventual contribution of missense variants is not known. While SRRM2 is known to encode a splicing factor promoting interaction between mRNA and the spliceosome catalytic machinery (discussed below) molecular and functional studies are required to characterize the pathogenesis of the disorder.

There is currently no SRRM2-related phenotype in OMIM. SRRM2 is included in the DD panel of G2P [confidence : definitive, SRRM2-related developmental disorder (monoallelic), cited : Kaplanis et al / DDD]. In PanelApp Australia SRRM2 has amber rating in the ID panel (based on the study by Kaplanis et al / DDD).

Consider inclusion with green rating (several individuals/families/variants - rather consistent phenotype) or amber rating (as for pathogenesis / also DD universal feature, ID observed in most but not all affected individuals, when present always mild).

-----

Cuinat et al. (2022 - PMID: 35567594) report on 22 individuals with LoF variants in SRRM2.

All subjects had DD (22/22) predominantly affecting language acquisition (16/19) while motor delay was less common. ID was present in 16/20 (in all cases mild) of the individuals with available neurocognitive evaluation. Some individuals displayed autistic features (9/22) although others had a friendly - in some cases excessively - sociable personality (8/22). Other features included hypotonia in some, growth abnormalities (12/22 overweight, 7/22 with obesity, 4/22 tall stature). Morphological features incl. facial (20/22 - e.g. deep-set eyes, bulbous nasal tip or smooth philtrum) or small hands and feet (6/22) were also reported. Visceral / skeletal abnormalities were uncommon.

SRRM2 encodes serine/arginine repetitive matrix protein 2 (or SRm300), a nuclear ubiquitous protein forming a complex with the protein encoded by SRRM1 (SRm160). As the authors summarize this complex is one of the main catalytic components of the spliceosome having a role in pre-mRNA maturation.

12 subjects harbored frameshift variants, 8 nonsense while 2 further ones had microdeletions (66-270kb) spanning - but not limited to - SRRM2 (other genes not predicted to be haploinsufficient). The gene has a pLI in gnomAD of 1 (o/e = 0.06) while it appears to be tolerant to missense variation (z-score of -6.28 / o/e = 1.43). With the exception of the 2 subjects harboring a microdeletion, all were investigated with singleton/trio ES with no other candidate variants.

Variants occurred de novo in 19/22. Mosaicism (in an asymptomatic parent) was suspected based on the reads in one case. One individual had inherited the variant (parent with DD). Segregation analyses was not possible in one case.

While one variant lied in ex2 (of 15) all others were in the large ex11 (encoding ~2000 of the 2752 total residues based on the schema provided / NM_016333.4), all predicted to lead to NMD.

There are no studies for pathogenesis of the disorder or the underlying effect of variants. Animal models not discussed.

The authors do a comparison with other 'spliceosomopathies', e.g. due to variants in SF3B4 or EFTUD2, where DD/ID can be a feature although these disorders have also prominent skeletal features.

Previously, as the authors note, the study by Kaplanis et al (2020 - PMID: 33057194) integrating exome sequence data from ~31,000 parent-offspring trios of individuals with developmental disorders had identified SRRM2 among 28 genes significantly enriched in LoF variants. [ The present study possibly includes individuals from the aforementioned cohort, e.g. from Radboudumc ].
Intellectual disability v3.1580 SRRM2 Konstantinos Varvagiannis reviewed gene: SRRM2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35567594, 33057194; Phenotypes: Global developmental delay, Intellectual disability, Behavioral abnormality, Abnormality of the head or neck, Small hand, Short foot; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1580 DROSHA Konstantinos Varvagiannis gene: DROSHA was added
gene: DROSHA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA 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: DROSHA was set to AMBER
Added comment: Profound DD, ID and seizures have been reported in 2 unrelated subjects with de novo missense variants. The gene has a role in miRNA biogenesis. Both variants described have been shown to have effect on DROSHA's function in Drosophila / C. elegans (partial loss-of-function vs possibility of antimorphic effect discussed || in gnomAD several individuals with LoF alleles / Z=3.98 – pLI : 0.09).

There is currently no DROSHA-related phenotype in OMIM, G2P, SysNDD. In PanelApp Australia the gene has amber rating in genetic epilepsy and microcephaly panels (not currently included in the ID one).

Consider inclusion in the current panel with amber rating. Also consider inclusion in other possibly relevant panels (given postnatal microcephaly, abn. corpus callosum, progressive white matter atrophy, etc) [ NOT added ]

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Barish, Senturk, Schoch et al (2022 - PMID: 35405010) describe the phenotype of 2 unrelated individuals with de novo missense DROSHA variants.

Features included generalized hypotonia, postnatal microcephaly (-2,6 and -6 SD), feeding difficulties, profound DD and ID, seizures, abnormal movements (choreoathetosis / stereotypic movements), variable respiratory symptoms (in one case episodes of hyperventilation/apnea), cardiovascular or skeletal findings. Brain MRI demonstrated white matter atrophy and thin corpus callosum in both. Brachycephaly with broad face as well as short feet were also among the shared features.

Both were investigated by trio ES/GS which were otherwise non diagnostic and without other candidate variants. The 1st individual harbored a de novo htz missense DROSHA variant (c.3656A>G/p.Asp1219Gly) while the 2nd subject had another missense variant (c.4024C>T/p.Arg1342Trp) [NM_013235.4] confirmed by Sanger seq.

DROSHA (on 5p13.3) encodes a ribonuclease, subunit of the microprocessor complex, involved in miRNA biogenesis. Specifically, miRNAs are transcribed as part of pri-miRNAs (primary-miRNAs) which are cleaved to pre-miRNAs (precursor-miRNAs) in the nucleus by DROSHA (and its partner DGCR8 or Pasha) and then exported to the cytoplasm for further processing. Cleavage of pre-miRNAs by DICER1 generates mature miRNAs subsequently loaded to the RISC (RNA-induced silencing) complex which uses miRNA as template for recognition and cleavage of complementary mRNA with RNAse.

As the authors discuss, miRNA defects have a well-established role in development of model organisms e.g. (several Refs. provided):
- in C. elegans miRNA mutants causing lethality, developmental arrest and heterochronicity
- in Drosophila playing a role in the development of ovary, eye, nervous system etc.
- in mice mRNAs play a role in BMP and TGF-beta signaling while neuronal loss of miRNA processing leads to neurodegeneration/anatomical defects.

Feingold syndrome 2 is the single Mendelian disease associated to date with miRNAs, through deletion of a cluster containing 6 MIR genes.

miRNA dysregulation is also observed in Rett syndrome - and DROSHA implicated in the pathogenesis of the syndrome - as MECP2 and FOXG1 are cofactors of the microprocessor complex regulating processing of miRNA. One of the individuals here reported had a clinical diagnosis of Rett spectrum while both had overlapping features with Rett s.

Studies of DROSHA-dependent miRNAs in fibroblasts from one individual revealed significantly altered expression of mature miRNA (e.g. increased miR98, a miRNA with reduced expression in studies of somatic DROSHA variants) although this was not likely due to processing errors (given only a modest decrease of precursor miRNAs).

Previous studies have demonstrated that drosha (the Drosophila ortholog) null mutants die during post-embryonic development with 100% lethality before adulthood (3rd instar larval stage/beginning of pupariation). Mosaic flies with mutant eyes are small-eyed, while viable hypomorphic alleles display synaptic transmission defects (several Refs provided).

Here, homozygous flies for null alleles died at the end of 3rd instar larval stage/beginning of pupariation, while loss of drosha resulted in lack of imaginal disc tissue (which surrounds the larval brain) and severely reduced brain size, the latter similar to the microcephaly phenotype. [To the best of my understanding] introduction of a mutated genomic rescue construct (carrying similar substitutions as those observed in human subjects) in eye-specific drosha null (W1123X) flies was partially able to rescue eye/head size for wt or Asp1219Gly (human:Asp1084Gly) suggesting that the latter is a partial LoF allele. Arg1210Trp (corresponding to human Arg1342Trp) was able to rescue the eye phenotype and was not damaging to the function in the specific assay. Drosha expression levels were similar for genomic rescue flies either for wt or for the Asp-Gly variant suggesting that the effect was not due to expression levels (but rather function). Expression of mature miRNAs known to be regulated by Drosha were not affected when comparing wildtype larvae with genomic construct for wt or Asp1084Gly.

Upon expression of human cDNA using GAL4/UAS system in drosha mutant (null) eye clones, the reference partially rescued the eye size defect, Asp-Gly behaved as partial loss-of-function allele (~50% function compared to ref), while the Arg-Trp variant was shown to behave as a weaker loss-of-function allele.

The authors generated eye-specific drosha mutant clones to study the aging adult eye using ERG recordings. While null mutants display almost no response to light (7- and 20-day old flies), wt genomic rescue was shown to rescue ERG responses, Asp-Gly variant had significant defects (at both 7 and 20 days) and the Arg-Trp had defects approaching statistical significance only at the age of 20 days. Overall these data suggested that Arg-Trp had less severe effect compared to Asp-Gly (as above) while both variants led to progressive neuronal dysfunction.

Using CRISPR/Cas9 the authors generated C.elegans knock-ins for a variant analogous to the Asp1219Gly human one. Homozygous animals were inviable at larval stages, displayed a heterochronic phenotype (heterochronicity : development of cells or tissues at an abnormal time relative to other unaffected events in an organism / miRNAs are known to be involved in the heterochronic gene pathway) while this variant was deleterious to the Drosha's ability to process miRNAs.
Sources: Literature
Intellectual disability v3.1580 SCAF4 Ian Berry reviewed gene: SCAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32730804; Phenotypes: Seizures, intellectual disability (mild); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1580 SOX11 Sarah Leigh Added comment: Comment on phenotypes: Described as MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=405).
Intellectual disability v3.1580 SOX11 Sarah Leigh Phenotypes for gene: SOX11 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27 to Coffin-Siris syndrome 9, OMIM:615866
Intellectual disability v3.1579 SOX11 Sarah Leigh Publications for gene: SOX11 were set to 24886874
Intellectual disability v3.1578 PRODH Sarah Leigh edited their review of gene: PRODH: Added comment: Evidence for the association of PRODH variants with Hyperprolinemia, type I, OMIM; 239500 has been classified as Definitive by ClinGen Aminoacidopathy Gene Curation Expert Panel on 04/27/2021
(https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5f28c677-a9b4-4bb3-9aed-14af97ad9896-2021-04-27T160000.000Z).; Changed rating: GREEN; Changed phenotypes to: Hyperprolinemia, type I, OMIM, 239500, hyperprolinemia type 1, MONDO:0009400
Intellectual disability v3.1578 PRODH Sarah Leigh Tag Q2_22_NHS_review tag was added to gene: PRODH.
Intellectual disability v3.1578 PRODH Sarah Leigh Tag Q2_22_rating tag was added to gene: PRODH.
Tag Q2_22_expert_review tag was added to gene: PRODH.
Intellectual disability v3.1578 PRODH Sarah Leigh Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, 239500; {Schizophrenia, susceptibility to, 4}, 600850 to Hyperprolinemia, type I, OMIM; 239500; {Schizophrenia, susceptibility to, OMIM:4}, 600850
Intellectual disability v3.1577 PRODH Sarah Leigh Publications for gene: PRODH were set to 12217952
Intellectual disability v3.1576 PRPF8 Konstantinos Varvagiannis gene: PRPF8 was added
gene: PRPF8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRPF8 were set to 35543142
Phenotypes for gene: PRPF8 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, MIM # 600059
Penetrance for gene: PRPF8 were set to unknown
Review for gene: PRPF8 was set to AMBER
Added comment: A recent study suggests that heterozygous PRPF8 variants are associated with a syndromic form of DD/ID, in some cases epilepsy with heterogeneous other clinical findings. However the authors acknowledge that not all variants within their cohort may be pathogenic (5 VUSs using ACMG criteria) and that conclusive evidence may necessitate functional studies.

Heterozygous variants (typically clustering in exon 42) have been reported to cause a non-syndromic form of RP with variable expressivity and incomplete penetrance (Retinitis pigmentosa 13, MIM # 600059) .

Overall consider inclusion with amber rating.

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O'Grady et al. (2022 - PMID: 35543142) describe the phenotype of 14 unrelated individuals with heterozygous, mostly de novo, missense and pLoF variants in PRPF8.

Nearly all had some degree of global developmental delay or ID (13/14). 6/14 had a diagnosis of ASD. Seizures were reported in 4 or 5 subjects. Other features included short stature (6/14), abnormal gait, cardiac anomalies and somewhat overlapping facial features (11/14). Ages ranged from 4 - 19 years (median : 9y).

PRPF8 encodes a component of the spliceosomes which in turn are involved in removal of introns from mRNA precursors. The gene is ubiquitously expressed with expression within brain being highest in cerebral cortex, basal ganglia and cerebellum (Refs. provided).

Individuals were investigated with exome sequencing (12/14) or an autism/ID panel of >2500 genes (likely application of virtual panel on exome data).

13 individuals harbored a missense SNV and 1 further had a frameshift variant. In 12 individuals the variant had occurred de novo. 1 individual had inherited the variant from a possibly mosaic parent, while for 1 further a single parental sample was available.

PRPF8 is intolerant to both missense (Z = 8.28) and pLoF variants (pLI : 1). Variants in 5 individuals were formally classified as VUS while 2 variants were present in gnomAD.

Additional findings (CNVs/SNVs) were reported, in some cases possibly of relevance.

As the authors discuss, heterozygous pathogenic missense SNVs cause (and account for ~2-3% of) non-syndromic AD retinitis pigmentosa with variable expressivity and incomplete penetrance. Variants for this phenotype are typically missense - although nonsense ones have also been reported - clustering within ex42 (of 43) encoding the MPN domain (aa 2103-2335 / NP_006436) and weakening interaction with 2 other spliceosomal proteins.

Variants in the present study occurred throughout the gene. Although not universally assessed within the cohort, only one participant had RP (in this case variant within the MPN domain).

There were no variant studies performed.

Animal models: the authors cite a study by Graziotto et al (2011 - PMID: 20811066) where knock-in mice for a missense variant in ex42 displayed defects of the retinal pigment epithelium. A zebrafish ko model also cited (Keightley et al, 2013 - PMID: 23714367) displayed widespread apoptosis in brain and spinal cord.

The authors cite a previous bioinformatic study identifying PRPF8 as a major hub connecting gene-interaction networks for NDDs (Casanova et al, 2018 - PMID: 30420816) as well as 2 studies demonstrating enrichment of variants in individuals with NDDs compared to controls (da Silva Montenegro et al, 2020 - PMID: 31696658, Karczewski et al, 2020 - PMID: 32461654).
Sources: Literature
Intellectual disability v3.1576 THUMPD1 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM or MONDO, but as moderate Gen2Phen gene for THUMPD1 neurodevelopment disorder. At least 7 variants have been reported, together with supportive functional studies (PMID: 35196516).; to: Not associated with a phenotype in OMIM or MONDO, but as moderate Gen2Phen gene for THUMPD1 neurodevelopment disorder. At least 8 variants have been reported in at least 7 unrelated cases, together with supportive functional studies (PMID: 35196516).
Intellectual disability v3.1576 THUMPD1 Sarah Leigh edited their review of gene: THUMPD1: Added comment: Not associated with a phenotype in OMIM or MONDO, but as moderate Gen2Phen gene for THUMPD1 neurodevelopment disorder. At least 7 variants have been reported, together with supportive functional studies (PMID: 35196516).; Changed rating: GREEN
Intellectual disability v3.1576 THUMPD1 Sarah Leigh Added comment: Comment on phenotypes: Phenotype name based on Gen2Phen entry (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4827).
Intellectual disability v3.1576 THUMPD1 Sarah Leigh Phenotypes for gene: THUMPD1 were changed from to THUMPD1 neurodevelopment disorder
Intellectual disability v3.1575 THUMPD1 Sarah Leigh Classified gene: THUMPD1 as Amber List (moderate evidence)
Intellectual disability v3.1575 THUMPD1 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 v3.1575 THUMPD1 Sarah Leigh Gene: thumpd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1574 THUMPD1 Sarah Leigh Tag Q2_22_rating tag was added to gene: THUMPD1.
Tag Q2_22_NHS_review tag was added to gene: THUMPD1.
Intellectual disability v3.1574 THUMPD1 Sarah Leigh Publications for gene: THUMPD1 were set to
Intellectual disability v3.1573 ZBTB7A Sarah Leigh edited their review of gene: ZBTB7A: Added comment: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least 11 variants have been reported in 10 unrelated cases.; Changed rating: GREEN
Intellectual disability v3.1573 ZBTB7A Sarah Leigh Phenotypes for gene: ZBTB7A were changed from Global developmental delay; Intellectual disability; Macrocephaly; Abnormality of the lymphatic system; Sleep apnea; Increased body weight; Autism; Persistence of hemoglobin F; Abnormal leukocyte count; Recurrent infections; Umbilical hernia to Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin, OMIM:619769
Intellectual disability v3.1572 ZBTB7A Sarah Leigh Classified gene: ZBTB7A as Amber List (moderate evidence)
Intellectual disability v3.1572 ZBTB7A 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 v3.1572 ZBTB7A Sarah Leigh Gene: zbtb7a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1571 ZBTB7A Sarah Leigh Tag Q2_22_rating tag was added to gene: ZBTB7A.
Tag Q2_22_NHS_review tag was added to gene: ZBTB7A.
Intellectual disability v3.1571 CELF2 Arina Puzriakova Classified gene: CELF2 as Amber List (moderate evidence)
Intellectual disability v3.1571 CELF2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 11 unrelated individuals harbouring heterozygous variants (10 de novo) in this gene. DD/ID observed in all cases, and although in some this was subsequent to onset of seizures, at least 2 individuals showed no epilepsy and therefore inclusion of CELF2 on this panel would be of value.
Intellectual disability v3.1571 CELF2 Arina Puzriakova Gene: celf2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1570 CELF2 Arina Puzriakova Tag Q2_22_rating tag was added to gene: CELF2.
Tag Q2_22_NHS_review tag was added to gene: CELF2.
Intellectual disability v3.1570 CELF2 Arina Puzriakova Publications for gene: CELF2 were set to 34107259; 33131106
Intellectual disability v3.1569 CELF2 Arina Puzriakova Phenotypes for gene: CELF2 were changed from Developmental delay; epileptic encephalopathy to Developmental and epileptic encephalopathy 97, OMIM:619561
Intellectual disability v3.1568 PHF14 Dmitrijs Rots gene: PHF14 was added
gene: PHF14 was added to Intellectual disability. Sources: Literature,Expert list
Mode of inheritance for gene: PHF14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHF14 were set to 35074918
Phenotypes for gene: PHF14 were set to Autism
Review for gene: PHF14 was set to GREEN
Added comment: Multiple individuals in the literature reported with NDD and de novo PHF14 variants + experimental findings (in 35074918).
Additional info from AutDB:"De novo missense variants in the PHF14 gene have been identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium cohort (Satterstrom et al., 2020), while additional rare de novo non-coding variation in this gene has also been observed in ASD probands (Sanders et al., 2015; Yuen et al., 2017). Zhou et al., 2022 reported that PHF14 forms a complex with MECP2 and TCF20; in the same report, the authors described two individuals with de novo variants in PHF14 who presented with neurodevelopmental phenotypes, including a patient with a de novo PHF14 missense variant that abolished the MECP2-PHF14-TCF20 interaction."
Sources: Literature, Expert list
Intellectual disability v3.1568 ABCC9 Arina Puzriakova Tag watchlist_moi tag was added to gene: ABCC9.
Intellectual disability v3.1568 ROBO1 Konstantinos Varvagiannis gene: ROBO1 was added
gene: ROBO1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ROBO1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ROBO1 were set to 35348658; 35227688; 34193621; 31448886; 30692597; 29194579; 28592524; 28402530; 28286008
Phenotypes for gene: ROBO1 were set to ROBO1-related NDD
Penetrance for gene: ROBO1 were set to unknown
Review for gene: ROBO1 was set to AMBER
Added comment: DD/ID has been reported in some individuals with biallelic (e.g. 4 subjects in the study by Münch et al, 1 additional case reported by Calloni et al) or monoallelic ROBO1 variants (e.g. P2 in the study by Huang et al, with a diagnosis of EOEE due to a neomorphic variant).

Consider amber rating pending further review.

------

Huang et al (2022 - PMID: 35348658) Monoallelic & Biallelic
Novel dominant and recessive variants in human ROBO1 cause distinct neurodevelopmental defects through different mechanisms.

Münch et al (2022 - PMID: 35227688) Biallelic
Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract

Woodring et al (2021 - PMID: 34193621) - Probably not relevant (VUS)
Uncertain, Not Unimportant: Callosal Dysgenesis and Variants of Uncertain Significance in ROBO1

Liu et al (2020 - PMID: 31448886) Monoallelic
A Novel Missense Mutation in Human Receptor Roundabout-1 (ROBO1) Gene Associated with Pituitary Stalk Interruption Syndrome.

Dateki et al (2019 - PMID: 30692597) Biallelic - This individual has been incl. in the study by Munch et al
A homozygous splice site ROBO1 mutation in a patient with a novel syndrome with combined pituitary hormone deficiency

Rasmussen et al (2018 - PMID: 29194579) Biallelic
Targeted gene sequencing and whole-exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

Kruszka et al (2017 - PMID: 28592524) Monoallelic
Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects

Bashamboo et al (2017 - PMID: 28402530) Monoallelic
Mutations in the Human ROBO1 Gene in Pituitary Stalk Interruption Syndrome

Calloni et al (2017 - PMID: 28286008) Biallelic
Compound Heterozygous Variants in ROBO1 Cause a Neurodevelopmental Disorder With Absence of Transverse Pontine Fibers and Thinning of the Anterior Commissure and Corpus Callosum
Sources: Literature
Intellectual disability v3.1568 CELF2 Julia Baptista gene: CELF2 was added
gene: CELF2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CELF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CELF2 were set to 34107259; 33131106
Phenotypes for gene: CELF2 were set to Developmental delay; epileptic encephalopathy
Mode of pathogenicity for gene: CELF2 was set to Other
Review for gene: CELF2 was set to GREEN
Added comment: De novo missense variants in six individuals (PMID:34107259). The variants cluster on the C‐terminus, a nuclear localization sign. Phenotypic findings include global developmental delay with moderate to severe impairment of speech and language capacities, infantile spasms, stereotypic movements and/or aggressive behaviors, and one individual was diagnosed with ASD.

A previous publication (PMID: 33131106) reported five unrelated individuals (four de novo). Two missense variants, one frameshift predicted to escape NMD and one splice site variant, c.272‐1G>C were identified; these variants, except the splicing, clustered on the C‐terminus.
Sources: Literature
Intellectual disability v3.1568 POLR3B Arina Puzriakova Mode of inheritance for gene: POLR3B was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1567 HIST1H4C Arina Puzriakova Publications for gene: HIST1H4C were set to 28920961
Intellectual disability v3.1566 HIST1H4C Arina Puzriakova Phenotypes for gene: HIST1H4C were changed from Growth delay, microcephaly and intellectual disability to Tessadori-van Haaften neurodevelopmental syndrome 1, OMIM:619758
Intellectual disability v3.1565 HIST1H4C Arina Puzriakova Mode of pathogenicity for gene: HIST1H4C 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 v3.1565 HIST1H4C Arina Puzriakova Mode of inheritance for gene: HIST1H4C was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1564 TAZ Arina Puzriakova commented on gene: TAZ
Intellectual disability v3.1564 TAZ Arina Puzriakova Tag new-gene-name tag was added to gene: TAZ.
Intellectual disability v3.1564 IMPAD1 Arina Puzriakova commented on gene: IMPAD1: Added new-gene-name tag, new approved HGNC gene symbol for IMPAD1 is BPNT2
Intellectual disability v3.1564 IMPAD1 Arina Puzriakova Tag new-gene-name tag was added to gene: IMPAD1.
Intellectual disability v3.1564 C8orf37 Arina Puzriakova commented on gene: C8orf37
Intellectual disability v3.1564 C8orf37 Arina Puzriakova Tag new-gene-name tag was added to gene: C8orf37.
Intellectual disability v3.1564 YIF1B Arina Puzriakova Tag gene-checked tag was added to gene: YIF1B.
Intellectual disability v3.1564 TTC5 Arina Puzriakova Tag gene-checked tag was added to gene: TTC5.
Intellectual disability v3.1564 RFX7 Arina Puzriakova Tag gene-checked tag was added to gene: RFX7.
Intellectual disability v3.1564 RFX4 Arina Puzriakova Tag gene-checked tag was added to gene: RFX4.
Intellectual disability v3.1564 RFX3 Arina Puzriakova Tag gene-checked tag was added to gene: RFX3.
Intellectual disability v3.1564 PTRHD1 Arina Puzriakova Tag gene-checked tag was added to gene: PTRHD1.
Intellectual disability v3.1564 PTPN4 Arina Puzriakova Tag gene-checked tag was added to gene: PTPN4.
Intellectual disability v3.1564 PRICKLE2 Arina Puzriakova Tag gene-checked tag was added to gene: PRICKLE2.
Intellectual disability v3.1564 PGM2L1 Arina Puzriakova Tag gene-checked tag was added to gene: PGM2L1.
Intellectual disability v3.1564 PCDHGC4 Arina Puzriakova Tag gene-checked tag was added to gene: PCDHGC4.
Intellectual disability v3.1564 NR4A2 Arina Puzriakova Tag gene-checked tag was added to gene: NR4A2.
Intellectual disability v3.1564 NCKAP1 Arina Puzriakova Tag gene-checked tag was added to gene: NCKAP1.
Intellectual disability v3.1564 ADD1 Konstantinos Varvagiannis gene: ADD1 was added
gene: ADD1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ADD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ADD1 were set to 34906466
Phenotypes for gene: ADD1 were set to Global developmental delay; Intellectual disability; Seizures; Ventriculomegaly; Abnormality of the corpus callosum
Penetrance for gene: ADD1 were set to unknown
Review for gene: ADD1 was set to AMBER
Added comment: A recent study suggests an ADD1-related phenotype (3 subjects with monoallelic de novo variants/1 with biallelic variants) with DD/ID and ventriculomegaly or corpus callosum dysgenesis and possibly seizures among the features.

There is currently no associated phenotype in other databases (OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the current panel with amber / green rating (3 subjects/variants/families, role of the gene and mouse models recapitulating ventriculomegaly/CC abnormalities, relevant expression, variant studies demonstrating abn. protein levels and/or disruption of adducin heterodimer formation || monoallelic vs bi-allelic variants).

Please consider inclusion in other possibly relevant gene panels (e.g. for corpus callosum / ventriculomegaly) [ Not added ].

--------

Qi et al (2022 - PMID: 34906466) describe the phenotype of 3 unrelated individuals with monoallelic de novo ADD1 pathogenic variants as well as of a fourth homozygous for a missense SNV.

Overall, the authors propose a common phenotype consisting of morphological brain abnormalities (incl. ventriculomegaly and corpus callosum dysgenesis) and neurological symptoms such as DD and/or ID and attention deficit.

All individuals were investigated with singleton/trio ES.

De novo variants - phenotype:
One individual investigated for hypotonia, DD & ID, partial ACC, well controlled seizures (on ketogenic diet) and proportional short stature harbored a de novo stopgain variant (NM_014189.3:c.1418G>A / p.Trp473*) absent from gnomAD.
Another affected subject with hypotonia, FTT/feeding difficulties, mild motor delays complete ACC, a seizure (2y11m), staring spells without EEG correlate, and fatigue (with low coenz. Q10, and complex I & IV deficiency in muscle biopsy) had a de novo fs variant (NM_001119:c.2029_2039del / p.Glu680Argfs*7 - gnomAD:0) and a VUS in a gene not associated with phenotype to date.
A 3rd subject investigated for seizures (onset:1y), speech delay, mild ID, ADHD, without MRI abnormalities harbored a de novo missense SNV (NM_001119:c.670C>T / p.His224Tyr - gnomAD:0) and with cmp htz for 2 missense SPTBN2 SNV not fitting the phenotype (no ataxia).

Biallelic variants - phenotype:
One individual with ID, and ACC, abnormal sulcation, enlarged lateral and 3rd ventricles, abnormal of white matter and hypoplastic vermis upon MRI was reported to harbor in homozygosity a missense SNV (NM_001119:c.169A>T / p.Arg57Trp). There was an additional variant in a gene without associated phenotype to date and not expressed in brain.

Role of the encoded protein:
ADD1 encodes adducin 1/alpha (similar to ADD2, ADD3 encoding other adducins). As the authors note, adducins are cytoskeleton proteins critical for osmotic rigidity and cell shape. In neurons they have been reported to form membrane associated periodic ring-like structures with actin and β-spectrin. Deletion of Add1 in mice results in increased MPS ring diameter and axonal degeneration (several refs provided).

ADD1/2/3 form heterodimers which in turn form heterotetramers. ADD1 is expressed in most tissues.

Mouse model:
Previous mouse models have demonstrated that Add1 null mice have also undetectable ADD2/3 (suggesting a role for stabilization of the latter) and exhibit growth delay, anemia and develop lethal hydrocephalus and ventriculomegaly with 50% penetrance (cited PMIDs: 27068466, 18723693). Here the authors demonstrated that surviving mice had ventriculomegaly and thinning of corpus callosum thus recapitulating the respective human phenotypes. Htz mice also presented thinner CC, though not to a statistically significant extent.

ADD1 expression and isoforms:
- Performing mRNA studies and W.Blot in (developing - GW15-17) human or mouse brain (E12.5-P40) the authors demonstrated dynamic expression of ADD1 with differentially expressed isoforms, notably alternative splicing of ex10 and ex15 with NM_176801 (extended ex10, inclusion of ex15) corresponding to a neuronal isoform and NM_001119 (shorter ex10, exclusion of ex15) corresponding to a neural progenitor cell (NPC) isoform.
- Variants here reported appear to affect both isoforms with the exception of NM_001119:c.2029_2039del / p.Glu680Argfs*7 affecting only the longer NPC one.
- PTBP1 is an RNA binding protein expressed in NPCs known to suppress neuronal exon insertion. The authors demonstrated in mouse Neuro2A cells, through shRNA targeting of Ptbp1, that the latter suppresses the neuronal Add1 isoform.

Variant studies demonstrated that effect of variants was mediated by decreased protein levels and/or disruption of adducin complex formation (ADD1-ADD2 dimer formation known to be mediated by N- and C- terminal ADD1 domains):
- Expression of Arg57Trp (found in hmz in one individual) NPC and neuronal isoforms in Neuro2a cells showed that while protein levels were not significantly affected, there were (also) truncated protein products for both isoforms suggesting that aberrant splicing or protein translation/cleavage may apply.
- The authors generated HEK293FT cells for the truncating variants demonstrating decreased protein levels (using N-/C- terminal antibodies).
- Reduced (HA-tagged)-ADD1-(V5-tagged)-ADD2 protein interaction was shown to apply for the Arg57Trp and Arg473* in HEK293FT cells. Similarly in Neuro2a cells, reduced ADD1-ADD2 interaction was shown for His224Tyr.
Sources: Literature
Intellectual disability v3.1564 THUMPD1 Julia Baptista reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35196516; Phenotypes: Intellectual disability, Microcephaly, Seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.1564 ZBTB7A Julia Baptista reviewed gene: ZBTB7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 34515416; Phenotypes: intellectual disability, macrocephaly, overgrowth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1564 SIN3B Eleanor Williams Tag gene-checked tag was added to gene: SIN3B.
Intellectual disability v3.1564 SMARCA5 Eleanor Williams Tag gene-checked tag was added to gene: SMARCA5.
Intellectual disability v3.1564 SNX27 Eleanor Williams Tag gene-checked tag was added to gene: SNX27.
Intellectual disability v3.1564 SVBP Eleanor Williams Tag gene-checked tag was added to gene: SVBP.
Intellectual disability v3.1564 SYNCRIP Eleanor Williams Tag gene-checked tag was added to gene: SYNCRIP.
Intellectual disability v3.1564 TBC1D2B Eleanor Williams Tag gene-checked tag was added to gene: TBC1D2B.
Intellectual disability v3.1564 TMEM222 Eleanor Williams Tag gene-checked tag was added to gene: TMEM222.
Intellectual disability v3.1564 TMEM94 Eleanor Williams Tag gene-checked tag was added to gene: TMEM94.
Intellectual disability v3.1564 CAMK4 Eleanor Williams Tag gene-checked tag was added to gene: CAMK4.
Intellectual disability v3.1564 CACNA1I Eleanor Williams Tag gene-checked tag was added to gene: CACNA1I.
Intellectual disability v3.1564 ATP9A Eleanor Williams Tag gene-checked tag was added to gene: ATP9A.
Intellectual disability v3.1564 ARFGEF1 Eleanor Williams Tag gene-checked tag was added to gene: ARFGEF1.
Intellectual disability v3.1564 RNU7-1 Eleanor Williams Tag gene-checked tag was added to gene: RNU7-1.
Intellectual disability v3.1564 PPP1R21 Eleanor Williams Tag gene-checked tag was added to gene: PPP1R21.
Intellectual disability v3.1564 PITRM1 Eleanor Williams Tag gene-checked tag was added to gene: PITRM1.
Intellectual disability v3.1564 NTNG2 Eleanor Williams Tag gene-checked tag was added to gene: NTNG2.
Intellectual disability v3.1564 BUB1 Konstantinos Varvagiannis gene: BUB1 was added
gene: BUB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BUB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1 were set to 35044816
Phenotypes for gene: BUB1 were set to Congenital microcephaly; Global developmental delay; Intellectual disability; Abnormal heart morphology; Growth delay
Penetrance for gene: BUB1 were set to Complete
Review for gene: BUB1 was set to AMBER
Added comment: A recent study provides evidence that this gene (biallelic variants) is relevant for inclusion in the DD/ID panel likely with amber / green rating (2 unrelated individuals with similar phenotype, 3 variants, role of this gene, extensive variant studies and demonstrated effects on cohesion and chromosome segregation, similarities with other disorders caused by mutations in mitosis-associated genes at the clinical and cellular level || number of affected subjects/families, different protein levels/kinase activity likely underlying few differences observed, role of monoallelic variants unclear).

This gene could probably be included in other panels e.g. for microcephaly (not added).

There is no BUB1-related phenotype in OMIM, G2P, SysID, PanelApp Australia.

------

Carvalhal, Bader et al (2022 - PMID: 35044816) describe the phenotype of 2 unrelated individuals with biallelic BUB1 pathogenic variants and provide evidence for the underlying mechanism for this condition.

Common features comprised congenital microcephaly (2/2 | -2,8 and -2.9 SDs respectively / -7 and -4,9 SDs on last evaluation), DD/ID (2/2 - in one case with formal evaluation mild), some degree of growth retardation (2/2) and cardiovascular findings (2/2 - small ASD type II). Other findings limited to one subject included Pierre-Robin sequence, Axenfeld-Rieger anomaly, choanal stenosis, hypospadias, tracheal stenosis, etc.

Initial genetic testing was normal (incl. CMA in both, metabolic testing and individual genes incl. PITX2, GREM1, FOXD3, FOXC1 for one proband).

Exome sequencing revealed homozygosity for a start-lost variant (NM_004336.4:c.2T>G / p.?) in the first subject (P1). The variant lied within a 14-Mb region of homozygosity (no reported consanguinity). The second individual (P2) was compound htz for a splice-site and a frameshift variant (c.2625+1G>A and c.2197dupG) with Sanger sequencing used for confirmation and segregation studies.

BUB1 encodes BUB1 Mitotic checkpoint serine/threonine kinase (/Budding uninhibited by benzimidazoles 1, s. cerevisiae, homolog of) a multifunctional component of the segregation machinery contributing to multiple mitotic processes. The protein has a kinetochore localization domain, multiple binding motifs and a C-terminal kinase domain (aa 784-1085) this structure allowing both kinase dependent/independent activities.

cDNA sequencing revealed that the splice variant leads to skipping of ex21 and in-frame deletion of 54 residues in the kinase domain (c.2625+1G>A / p.Val822_Leu875del).

Both individuals exhibited normal BUB1 mRNA levels (fibroblasts in both, tracheal tissue in one) but severely reduced protein levels (fibroblasts). A shorter protein product corresponding to the in-frame deletion variant was also detected.

The authors performed additional experiments to confirm small amounts of full-length protein produced by the start-lost variant. This was shown in SV40-transformed fibroblasts from the corresponding individual (treatment with a proteasome inhibitor resulted also in higher levels). Upon generation RPE1 cells using CRISPR for the start-lost variant, again, small amounts of full length protein were detected, which was not the case for complete knockout HAP1 cells. No shorter versions could be detected in the patient cells or RPE1 cells, arguing against utilization of an alternative start codon. (Use of non-AUG start codons discussed based on literature).

In line with small amounts of full-length protein the authors provided evidence for residual kinase activity for the start-loss variant (through proxy of phosphorylation of its substrate and use of a BUB1 kinase inhibitor). Cells from the individual with the frameshift variant and the splice variant had no residual kinase activity.

The authors provide evidence for mitotic defects in cells from both individuals with prolonged mitosis duration and chromosome segregation defects. Some patient-specific findings were thought to be related with BUB1 protein levels (affecting BUB1-mediated kinetochore recruitment of BUBR1, important for chromosome alignment) and others due to residual kinase activity [->phosphorylation of H2A at Threonine 120-> affecting centromeric recruitment of Aurora B, SGO1 (role in protection of centromeric cohesion), TOP2A (a protein preventing DNA breakage during sister chromatid separation), these correlated with high anaphase bridges (in P2), aneuploidy observed in lymphoblasts and primary fibroblasts from P2 but not P2's lymphocytes or lymphocytes from P1) and defective sister chromatid cohesion defects (in primary fibroblasts from P2, milder effect for P1).

Overall the authors provide evidence for overlapping clinical and cellular phenotype for this condition with primary microcephalies (MCPH - mutations in genes for mitotic regulators incl. kinetochore proteins or regulators of chromosome organization), mosaic variegated aneuploidy (biallelic variants in genes for kinetochore proteins, with random aneuploidies occurring in >5% cells of different tissues) and cohesinopathies (mostly Roberts or Warsaw breakage syndromes - characterized by cohesion loss and/or spontaneous railroad chromosomes).

Mouse model: Hmz disruption in mice is lethal shortly after E3.5 (cited PMID: 19772675), while a hypomorphic mutant mouse (lacking exons 2-3, expressing <5% of wt protein levels) is viable but exhibits increased tumorigenesis with aging and aneuploidy (cited PMID: 19117986). Mutant mice that lack kinase activity though with preserved Bub1 protein abundance, did not display increased susceptibility, despite substantial segregation errors and aneuploidies (cited PMID: 23209306).

The authors note that monoallelic germline BUB1 variants have been described in small number of individuals with CRC, exhibiting reduced expression levels and variegated aneuploidy in multiple tissues (cited PMID: 23747338) although the role of BUB1 is debated (cited PMIDs: 27713038, 29448935).

Based on the discussion, complete loss of BUB1 activity is presumed to be embryonically lethal based on the mouse study (PMID: 19772675) and reduced BUB1 expression associated with spontaneous miscarriages (cited PMID: 20643875, to my understanding in this study mRNA levels remained relatively constant despite reduced Bub1 protein levels, mRNA RT-PCR followed by sequencing revealed only 2 synonymous BUB1 variants).
Sources: Literature
Intellectual disability v3.1564 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from developmental delay to Combined oxidative phosphorylation deficiency 35, OMIM:617873
Intellectual disability v3.1563 TRIT1 Eleanor Williams Tag gene-checked tag was added to gene: TRIT1.
Intellectual disability v3.1563 TRPM3 Eleanor Williams Tag gene-checked tag was added to gene: TRPM3.
Intellectual disability v3.1563 METTL5 Eleanor Williams Tag gene-checked tag was added to gene: METTL5.
Intellectual disability v3.1563 LMBRD2 Eleanor Williams Tag gene-checked tag was added to gene: LMBRD2.
Intellectual disability v3.1563 WDR37 Eleanor Williams Phenotypes for gene: WDR37 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system; Neurooculocardiogenitourinary syndrome, OMIM:618652
Intellectual disability v3.1562 WDR37 Eleanor Williams Tag gene-checked tag was added to gene: WDR37.
Intellectual disability v3.1562 ZNF526 Eleanor Williams Tag gene-checked tag was added to gene: ZNF526.
Intellectual disability v3.1562 HPDL Eleanor Williams Tag gene-checked tag was added to gene: HPDL.
Intellectual disability v3.1562 FBRSL1 Eleanor Williams Tag gene-checked tag was added to gene: FBRSL1.
Intellectual disability v3.1562 CCDC47 Eleanor Williams Tag gene-checked tag was added to gene: CCDC47.
Intellectual disability v3.1562 CXorf56 Eleanor Williams Tag gene-checked tag was added to gene: CXorf56.
Intellectual disability v3.1562 CEP85L Eleanor Williams Tag gene-checked tag was added to gene: CEP85L.
Intellectual disability v3.1562 PABPC1 Konstantinos Varvagiannis gene: PABPC1 was added
gene: PABPC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PABPC1 were set to 35511136
Phenotypes for gene: PABPC1 were set to Global developmental delay; Expressive language delay; Intellectual disability; Behavioral abnormality; Seizures
Penetrance for gene: PABPC1 were set to unknown
Review for gene: PABPC1 was set to AMBER
Added comment: Wegler et al (2022 - PMID: 35511136) describe the phenotype of 4 individuals with de novo variants in the PABP domain of PABPC1.

Overlapping features included DD (4/4) with weak expressive language (4/4), learning disability/borderline intellectual functioning (in 2) to more severe ID (in 2 others), treatable/self-limiting seizures (in 3 for whom this information was available) as well as variable behavioral issues (impaired social skills, concentration/sleeping problems, ADHD, anxiety or autism). Other features involved feeding difficulties (3/4), hearing impairment (in 2/3) or variable other phenotypes. Contribution of de novo variants found in other genes was thought possible.

All 4 were investigated by trio exome sequencing following negative previous routine diagnostic work-up. WES revealed heterozygous de novo PABPC1 variants, 3 of which were missense SNVs (c.1687G>A/p.Gly563Ser, c.1691A>C/p.Glu564Gly, c.1709T>C/p.Ile570Thr using NM_002568.3) and a fourth an in-frame deletion (c.1664_1666del/p.Pro555del).

Additional de novo variants were reported in 3 cases (IGF2R missense SNV, htz KDM5B stopgain, RBBP4 - the latter not associated with any phenotype to date).

PABPC1 encodes Polyadenylate-binding protein, cytoplasmic, 1 which as the authors summarize has an important role overall in regulation of gene expression (poly(A) tail length, mRNA formation, export of processed mRNAs to cytoplasm, translation initiation promotion and termination, mRNA stability, NMD). Translation is regulated by Polyadenylate-binding protein–interacting proteins (PAIPs) which control PABP activity. PAIP2 in particular, which is highly expressed in CNS, is known to inhibit translation via binding to the PABP domain of PABPC1 and is thought to play an important role through transcriptional regulation for synaptic plasticity and memory.

To evaluate plausibility as a DD gene the authors performed analyses using publicly available data, with PABPC1 ranking high in terms of protein-protein interaction (PPI) and co-expression with known DD genes.

Variants were absent from gnomAD with in silico predictions in favour of a deleterious effect.

While PABPC1 is intolerant to both missense and LoF variants (z-score 4.49, pLI of 1), occurrence of these 4 dn variants and their clustering in the PABP domain appeared to be of statistical significance (p=0.002 and p=2.8x10-8) rather than being explained by random occurrence.

Structural modeling of variants suggested that all were in close spatial vicinity within the PABP domain, likely influencing PAIP2 binding.

In HeLa cells the variants were shown not to affect subcellular localization (to the cytoplasm) compared to wt. In addition, there were no significant differences upon stress conditions under which the protein localizes to stress granules.

In HeLa cells, co-immunoprecipitation assays using C-terminal HA tagged PABPC1, revealed that 3 variants (Gly563Ser, Glu564Gly, Ile570Thr) significantly reduced physical PABPC1-PAIP2 interaction compared with wt, which was also observed though to a not significant extent for Pro555del. (Other variants from literature also studied as discussed below).

Pabpc1 is highly expressed in all regions of the developing mouse brain with remarkable decrease after birth, suggesting a critical role in prenatal brain development. Through electroporation with Pabpc1-directed shRNA the authors provided evidence that Pabpc1 LoF results in abnormal neural progenitor cell proliferation with rescue experiments using human WT or missense variants (Gly563Ser, Glu564Gly, Ile570Thr) showing that only the WT could rescue the proliferation phenotype.

Overall a model whereby weakened PABPC1-PAIP2 interaction, leading to dysregulation to gene expression homeostasis and interference with proliferation of neural progenitors and the later to the NDD phenotype is proposed.

Given previous reports in the literature for de novo PABPC1 variants, namely Lys138Glu, Asp204Val, Arg481His, Pro456Leu the authors noted that the phenotypes reported in the respective individuals were rather explained by other variants (16p11.2 dup, ARID1A dn, TBL1XR1 dn variants). These PABPC1 variants do not lie in the PABP domain, have lower in silico pathogenicity scores (MPC/CADD), with structural modelling suggestive of no significant effect. Importantly, upon co-immunoprecipitation studies with PAIP2 which were here performed, these variants had no effect. Pathogenicity of these variants - not located within the PABP domain - through another mechanism cannot be however ruled out. (PMIDs cited, though not reviewed based on this discussion: De Rubeis et al, 2014 - PMID: 25363760, Guo et al, 2019 - PMID: 30504930, Kaplanis et al, 2020 - PMID: 33057194).

Currently there is no PABPC1-related phenotype in other databases (incl. OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the gene panels for ID and epilepsy with amber / green rating (DD with or without ID in >= 3 individuals/families/variants – also the case for seizures, role of the gene, statistical evidence for the gene/occurrence and clustering of variants, functional studies with strong evidence for at least 3 variants || learning difficulties/borderline intellectual functioning in 2 affected individuals, phenotype in few might be "blended" due to additional de novo variants).
Sources: Literature
Intellectual disability v3.1562 CTR9 Konstantinos Varvagiannis reviewed gene: CTR9: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 35499524, 2815719, 25363760, 27479843, 25099282, 29292210; Phenotypes: Delayed speech and language development, Motor delay, Intellectual disability, Behavioral abnormality, Autistic behavior, Failure to thrive, Feeding difficulties, Abnormality of the cardiovascular system; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1562 CTR9 Konstantinos Varvagiannis Deleted their review
Intellectual disability v3.1562 CTR9 Konstantinos Varvagiannis gene: CTR9 was added
gene: CTR9 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CTR9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTR9 were set to 35499524; 2815719; 25363760; 27479843; 25099282; 29292210
Phenotypes for gene: CTR9 were set to Delayed speech and language development; Motor delay; Intellectual disability; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system
Penetrance for gene: CTR9 were set to unknown
Mode of pathogenicity for gene: CTR9 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: CTR9 was set to AMBER
Added comment: Meuwissen, Verstraeten, Ranza et al (2022 - PMID: 35499524) describe the phenotype of 13 unrelated individuals harboring heterozygous - predominantly de novo - CTR9 missense variants.

Overlapping features included delayed speech and/or motor development (each in 9 cases) with the latter complicated by hypotonia or hyperlaxity in some cases. Balance or coordination problems were also reported in some. Variable degrees of ID ranging from mild to severe were observed in all individuals of relevant age except for 3 who however experienced impairment in other domains and/or learning difficulties (8/11 - 2 individuals were too young for evaluation). Few had evidence of regression. Other features included behavioral abnormalities (incl. ASD in 4), FTT/feeding problems (in 5), cardiovascular findings (in 4 - incl. infantile thoracic aortic aneurysm, VSD, pulm. valve stenosis, SVAS). The authors reported variable/nonspecific dysmorphic features.

WES revealed heterozygous CTR9 missense variants in all cases (NM_014633.5 as RefSeq). The variants occurred de novo in most (11/13) individuals with a one proband having inherited the variant from his affected parent. For one case, a single parental sample was available. Most SNVs were absent from gnomAD with the exception of c.1364A>G/p.Asn455Ser and c.2633G>A/p.Arg878Gln present once in the database (Z-score for CTR9: 4.3 / pLI : 1). The variants affected highly conserved residues with in silico predictions mostly in favor of a deleterious effect.

CTR9 encodes a subunit of the PAF1 complex (PAF1C) with the other subunits encoded by PAF1, LEO1, CDC73, RTF1 and WDR61/SKI8. The complex acts as a transcriptional regulator with CTR9 binding RNA polymerase II. The complex influences gene expression by promoting H2BK123 ubiquitylation, H3K4 and H3K36 methylation. In yeast, Paf1 and Ctr9 appear to mediate involvement of Paf1C in induction of mitophagy (several Refs provided).

In silico modeling: a group of N-terminal variants likely destabilize structure, another group possibly perturbs CTR9-PAF1 interactions and a 3rd class influences interactions with other subunits. p.Glu15Lys did not appear to influence protein stability.

Functional studies: H3K4/H3K36 methylation analysis, mitochondrial quality assessment and RNA-seq studies in fibroblasts did not provide conclusive evidence for downstream consequences of the variants (albeit a brain-specific effect - as demonstrated for other disorders – cannot be excluded).

Animal models: In zebrafish, the Paf1C complex has been shown to play a role in cardiac specification and heart morphogenesis with ctr9 mutants showing severe defects in morphogenesis of primitive heart tube (cited PMID: 21338598). This supports a role of the CTR9 variants in the cardiac abnormalities observed in 4 individuals. Although Paf1C zebrafish homologues are required for Notch-regulated transcription (cited PMID: 17721442), there was no supporting evidence from RNA-seq analyses performed by the authors. In Drosophila, Ctr9 has a key role at multiple stages of nervous system development in Drosophila (cited PMID: 27520958). In rat, Ctr9 is expressed in dopaminergic neurons, with its expression not restricted to the nucleus, regulating dopamine transporter activity (cited PMID: 26048990).

As commented, de novo CTR9 variants have been identified in indivdiduals with developmental disorders in larger cohorts, though without phenotypic details (DDD study - PMID:2815719, De Rubeis et al, 2014 - PMID: 25363760, Lelieveld et al PMID: 27479843) [ https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=CTR9 ]

Two previous studies (Hanks et al, 2014 - PMID: 25099282, Martins et al 2018, PMID: 29292210) have identified individuals with pLoF variants [in almost all cases leading to skipping of ex9 e.g. NM_014633.4:c.958-9A>G or (RefSeq not provided) c.1194+2T>C, c.1194+3A>C, the single exception being c.106C>T/p.Q36*] in individuals and families with Wilms tumor after exclusion of other genetic causes. Analyses of tumor samples revealed in several of these cases either LOH (most commonly) or truncating variants as second hits. These individuals did not display neurodevelopmental phenotypes (despite detailed clinical information provided in the 2 studies). CTR9 is included in the gene panels for WT and Tumor predisposition - childhood onset with green rating. [In addition few individuals with hyperparathyroidism jaw tumor syndrome due to heterozygous variants in CDC73 - another subunit of the PAF1 complex - have been reported with WT].

Given these reports, commenting on the embryonic lethality of Ctr9 homozygous ko mice (MGI) and the observation of only missense variants in their cohort Meuwissen, Verstraeten, Ranza et al presume that a dominant-negative effect may apply for the variants they report.

Consider inclusion in the current panel with amber (variant effect/underlying mechanism unknown) or green rating (>3 individuals/families/variants, multiple reports, some supporting evidence from animal models).
Sources: Literature
Intellectual disability v3.1562 MPP5 Arina Puzriakova Tag gene-checked tag was added to gene: MPP5.
Intellectual disability v3.1562 LINGO4 Arina Puzriakova Tag gene-checked tag was added to gene: LINGO4.
Intellectual disability v3.1562 KLF7 Arina Puzriakova Tag gene-checked tag was added to gene: KLF7.
Intellectual disability v3.1562 KIF21B Arina Puzriakova Tag gene-checked tag was added to gene: KIF21B.
Intellectual disability v3.1562 KCND2 Arina Puzriakova Tag gene-checked tag was added to gene: KCND2.
Intellectual disability v3.1562 JARID2 Arina Puzriakova Tag gene-checked tag was added to gene: JARID2.
Intellectual disability v3.1562 AGO1 Eleanor Williams Tag gene-checked tag was added to gene: AGO1.
Intellectual disability v3.1562 HNRNPH1 Arina Puzriakova Tag gene-checked tag was added to gene: HNRNPH1.
Intellectual disability v3.1562 HID1 Arina Puzriakova Tag gene-checked tag was added to gene: HID1.
Intellectual disability v3.1562 ZBTB7A Julia Baptista Deleted their review
Intellectual disability v3.1562 ZBTB7A Julia Baptista reviewed gene: ZBTB7A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:34515416; Phenotypes: intellectual disability, macrocephaly, overgrowth; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1562 KCTD3 Arina Puzriakova Tag gene-checked tag was added to gene: KCTD3.
Intellectual disability v3.1562 HNRNPR Arina Puzriakova Tag gene-checked tag was added to gene: HNRNPR.
Intellectual disability v3.1562 GNAI1 Arina Puzriakova Tag gene-checked tag was added to gene: GNAI1.
Intellectual disability v3.1562 GNAI1 Arina Puzriakova Phenotypes for gene: GNAI1 were changed from GNAI1 syndrome to Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, OMIM:619854
Intellectual disability v3.1561 CSNK1G1 Sarah Leigh Tag gene-checked tag was added to gene: CSNK1G1.
Intellectual disability v3.1561 CSDE1 Sarah Leigh Tag gene-checked tag was added to gene: CSDE1.
Intellectual disability v3.1561 CHD5 Sarah Leigh Tag gene-checked tag was added to gene: CHD5.
Intellectual disability v3.1561 BRSK2 Sarah Leigh Tag gene-checked tag was added to gene: BRSK2.
Intellectual disability v3.1561 BRD4 Sarah Leigh Tag gene-checked tag was added to gene: BRD4.
Intellectual disability v3.1561 ACTL6A Sarah Leigh Tag gene-checked tag was added to gene: ACTL6A.
Intellectual disability v3.1561 DNAH14 Konstantinos Varvagiannis gene: DNAH14 was added
gene: DNAH14 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DNAH14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH14 were set to 35438214
Penetrance for gene: DNAH14 were set to unknown
Review for gene: DNAH14 was set to RED
Added comment: Li et al (2022 - PMID: 35438214) describe 3 individuals harboring biallelic DNAH14 variants. In addition the authors perform a review of cases previously published in the literature.

The reported phenotype does not appear to be very consistent or specific (seizures with highly variable age of onset with or without DD / cognitive delay). Comparison with previously reported subjects (not further reviewed) - discussed in text and appearing mixed in table 1 - does not seem to support an overlapping phenotype.

The authors comment that DNAH14 encodes a heavy chain of axonemal dyneins. Little evidence is provided to support the role of the gene in the pathogenesis of the disorder and pathogenicity of the variants (ultra-rare and predicted in silico to be deleterious).
Sources: Literature
Intellectual disability v3.1561 DALRD3 Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature; to: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES in both followed by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.

Sources: Literature
Intellectual disability v3.1561 DALRD3 Konstantinos Varvagiannis gene: DALRD3 was added
gene: DALRD3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DALRD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DALRD3 were set to 32427860
Phenotypes for gene: DALRD3 were set to ?Developmental and epileptic encephalopathy 86, # 618910
Penetrance for gene: DALRD3 were set to Complete
Review for gene: DALRD3 was set to AMBER
Added comment: Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES guided by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.
Sources: Literature
Intellectual disability v3.1561 DPH5 Konstantinos Varvagiannis gene: DPH5 was added
gene: DPH5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH5 were set to 35482014
Phenotypes for gene: DPH5 were set to Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck
Penetrance for gene: DPH5 were set to unknown
Review for gene: DPH5 was set to AMBER
Added comment: Shankar et al (2022 - PMID: 35482014) present evidence for a diphthamide-deficiency syndrome due to biallelic DPH5 pathogenic variants.

As the authors summarize, DPH5 encodes a methyltransferase critical to the biosynthesis of diphthamide. Diphthamide is a post translationally modified histidine residue found in eukaryotic elongation factor 2 (eEF2). eEF2 is essential for mRNA translation and protein synthesis. The role of diphthamide is not clear, although it serves as a target for ADP-ribosylation, the latter resulting in inactivation of the eEF2 (inhibition of its translocation activity) and arrest of protein synthesis. Biosynthesis of diphthamide is complex involving multiple components (DPH1-DPH7) and the methylating co-factor S-adenosyl methionine, with 2 diphthamide-deficiency disorders due to biallelic DPH1 or DPH2 pathogenic variants and a NDD phenotype reported to date.

The authors describe a phenotypic spectrum associated with biallelic DPH5 variants ranging from a prenatally lethal presentation to profound neurodevelopmental disorder. Details are provided on 5 individuals from 3 unrelated families. While one subject died at the age of few days due to multisystem complications, the phenotype appeared to be relatively consistent with prenatal findings (decreased fetal movements in 2 from 2 families, polyhydramnios in 2 from 2 families), hypotonia, global DD and ID (4/4 from 2 families - profound in 3), seizures (3/5 from 2 families - abnormal EEG in 4/4), cardiovascular findings (5/5, MVP and regurgitation in 2 from Fam1 || aortic dilatation in 2 sibs from Fam2 || VSD, ASD and hypopl. PA, pericardial effusion in 5th), GI issues (5/5, poor feeding in 4), short stature (4/4). Ocular findings were reported in 3/4 (gray sclerae in 2, ocular melanocytosis in 2). The authors describe some common craniofacial findings incl. broad/prominent forehead (5/5), sparse eyebrows (4/5), downturned corners of mouth or triangular chin (each in 3/5).

WES/WGS revealed biallelic DPH5 variants in all affected individuals, namely: homozygosity for a missense variant in 2 sibs (NM_001077394.2:c.779A>G/p.His260Arg). Homozygosity for c.521dupA/p.Asn174LysTer10 for the individual deceased in the neonatal period (for this family there was significant history of spontaneous miscarriages/stillbirth/neonatal death). Two sibs born to non-consanguineous parents were compound htz for a stopgain and a missense SNV (c.619C>T/p.Arg207*, c.329A>G/p.Asn110Ser).

In silico modeling revealed that the pLoF variants, not predicted to lead to NMD, likely remove the domain for interaction with eEF2 while the missense ones also affected interaction with eEF2.

In recombinant MCF7 breast cancer cell line-derived DPH5-knockouts, transfected with recombinant expr. plasmids encoding wt or the 4 variants, the 2 truncating variants were shown to affect ADP-ribosylation of eEF2's diphthamide (total lack / minimal enzymatic activity for Arg207* and Asn174Lysfs respectively). Asn110Ser and His260Arg had residual activities which was thought to be explained by high expression levels compensating partial inactivation (given the multicopy plasmid-driven expression).

ADP-ribosylation assays in S. cerevisiae demonstrated loss of function for the 2 truncating variants. Although the 2 missense variants retained sufficient activity to produce diphthamide (assayed through toxin induced ADP-ribosylation of eEF2), more sensitive assays indicated that diphthamide synthesis was also partially compromised for both variants.

Generation of a knockin mouse model for His260Arg, appeared to recapitulate the human phenotypes with craniofacial, ophthalmologic, cardiac and visceral abnormalities and hmz mice being subviable. A single homozygous liveborn mouse had low birthweight, FTT, craniofacial dysmorphology, polydactyly, abnormal grooming behavior and early death. Few heterozygous embryos had craniofacial features, decreased body weight, reduced neuromuscular function without other abnormalities, either due to their inbred background or in the context of milder phenotype of heterozygosity in mice.

DPH5 is ubiquitously expressed in all human tissues. The gene has a pLI of 0 and LOEUF score of 0.77 (0.48-1.27) in gnomAD. The authors refer to unpublished data, noting that complete absence of DPH5 is incompatible with life with embryonic lethality of a Dph5(ko/ko) line.

The phenotype bears similarities to DPH1- and DPH2- related NDDs (both AR / green and amber respectively in ID panel) and appears to be more severe compared to the phenotype of de novo EEF2 variants (cited PMID: 33355653).

Please consider inclusion in the ID panel with amber (4 individuals from 2 families with ID) / green rating (rather consistent phenotype in 3 families probably representing a continuous spectrum, variant studies, mouse model, similarities with diphthamide-deficiency syndromes). Also consider amber rating in the epilepsy panel (3 individuals from 2 families reported). The gene may be also relevant in other gene panels e.g. for congenital heart disease, short stature, etc (not added).
Sources: Literature
Intellectual disability v3.1561 CCDC82 Konstantinos Varvagiannis gene: CCDC82 was added
gene: CCDC82 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC82 were set to 27457812; 28397838; 35118659; 35373332
Phenotypes for gene: CCDC82 were set to Global developmental delay; Intellectual disability; Spastic paraparesis
Penetrance for gene: CCDC82 were set to Complete
Review for gene: CCDC82 was set to AMBER
Added comment: The phenotype of individuals with biallelic CCDC82 variants has been reported - in most cases briefly - in the following reports (each summarizing the findings of previous ones):

Riazzudin et al (2017 - PMID: 27457812) in a large consanguineous pedigree from Pakistan (PKMR206) identified 4 individuals homozygous for a fs variant [NM_024725.3:c.373delG / p.(Asp125Ilefs*6)] (V3,V4,V5,V10). There was no other variant segregating with the phenotype of ID (Delayed CMS, moderate ID and speech delay probably common to all, V3,4,5 had also mild hypotonia and motor weakness). There was one unaffected sib tested (homozygous for ref. alelle). 2 further affected males (V1, V2) with similar phenotype were not tested.

Harripaul et al (2018 - PMID: 28397838) reported 2 sibs with nonsyndromic ID belonging to a consanguineous family (AS17) from the Middle-East. Both were homozygous for NM_024725.3:c.535C>T / p.Arg179*. The variant was confirmed with Sanger sequencing and parents were heterozygous carriers. Two additional affected sibs were probably not tested.

Yahia et al (2022 - PMID: 35118659) described 2 sibs belonging to a consanguineous family from Sudan. These presented global DD (last evaluation at 4y and 9m) and spasticity. There was a common history of infantile spasms with the elder developing GTC convulsions with spontaneous resolution. Additionaly, both presented microcephaly (<-2 and <-3SD). Exome sequencing revealed homozygosity for c.535C>T / p.Arg179* (previously reported by Harripaul et al). Sanger sequencing was used for confirmation and demonstration of carrier state of parents. Two similarly affected sibs were not available for testing.

Bauer et al (2022 - PMID: 35373332) reported a 21 y.o. male born to consanguineous parents from Pakistan. Features included short stature, ID, spastic paraparesis (at the age of 3y). Gelastic seizures were suspected but not confirmed (repeated normal EEGs). WES revealed homozygosity for a fs CCDC82 variant [NM_001318736.1:c.183del / p.(Phe61Leufs*27)] with Sanger confirmation in proband and heterozygous parents. There was another hmz variant, albeit classified as VUS and not thought to fit the clinical presentation.

As proposed by Bauer et al. overlapping features include spastic paraparesis, DD and dysmorphic features. As commented, CCDC82 encodes coiled-coil domain protein 82, a protein with unknown function.

Consider inclusion probably with amber rating (>3 individuals/families/variants, role of the gene not known, variant studies not performed to date, animal models not discussed).
Sources: Literature
Intellectual disability v3.1561 ENTPD1 Konstantinos Varvagiannis reviewed gene: ENTPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35471564; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1561 PRODH Tracy Lester reviewed gene: PRODH: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disabilty; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1561 FBXO28 Konstantinos Varvagiannis gene: FBXO28 was added
gene: FBXO28 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXO28 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXO28 were set to 30160831; 33280099
Phenotypes for gene: FBXO28 were set to Developmental and epileptic encephalopathy 100 (# 619777)
Penetrance for gene: FBXO28 were set to unknown
Review for gene: FBXO28 was set to GREEN
Added comment: Heterozygous pathogenic FBXO28 variants cause Developmental and epileptic encephalopathy 100 (# 619777).

At least 10 individuals with monoallelic missense / truncating FBXO28 variants have been reported. The subject with de novo frameshift variant initially reported by Balak et al (2018 - PMID:30160831) was included with additional clinical details in a recent report along with 9 further individuals (Schneider et al, 2021 - PMID: 33280099).

The phenotype corresponds to a developmental and epileptic encephalopathy with severe/profound ID. As discussed by Schneider et al, all individuals had DD prior to seizure onset which occurred at a median age of 22.5 months (range: 8m - 5y). The authors noted that missense variants may be associated with a milder phenotype (e.g. seizures occurred at the age of 4-5 years in 3 individuals).

Given these, FBXO28 appears to be relevant for inclusion in the current panel, with investigations prior to seizure onset.

As in the summary by Schneider et al, the gene encodes F-box only protein 28, a ubiquitin ligase promoting ubiquitination and degradation of phosphorylated proteins.

While FBXO28 has been suggested to have a critical role in 1q41q42 deletions (most spanning also WDR26) the authors note that a mechanism different than haploinsufficiency may underly FBXO28 encephalopathy.

Importantly, all 5 truncating variants reported (and 2/4 missense ones) occurred in the last exon, making these variants less susceptible to NMD. 2 other (of the 4) missense variants clustered in the F-box domain, which the authors hypothesize may correspond to a second pathogenic region.

7/9 variants arose de novo while 2 individuals had inherited a missense and a stopgain variant from mosaic unaffected parents (2.5% and 6%).

A comparison of the FBXO28-associated phenotype with the respective of 1q41q42 deletions and WDR26-related NDD is also made.

Consider inclusion in the ID panel with green (or amber) rating. Please consider inclusion in other possibly relevant panels (e.g. microcephaly (4/10), movement disorders, etc).
Sources: Literature
Intellectual disability v3.1561 GJB2 Dmitrijs Rots reviewed gene: GJB2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1561 CCDC32 Konstantinos Varvagiannis reviewed gene: CCDC32: Rating: AMBER; Mode of pathogenicity: None; Publications: 32307552, 35451546; Phenotypes: Cardiofacioneurodevelopmental syndrome (# 619123); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1561 CDK9 Konstantinos Varvagiannis changed review comment from: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity.

After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824).
Sources: Literature; to: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance due to consanguinity.

Using autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in one case). Overall, the authors used the term CHARGE-like for this phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with ophthalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two of them), heart defect (2/3 with VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags in 2/3, bilateral deafness 1/3, bilateral ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 | suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with several in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacting with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited : 27715402, 30100824).
Sources: Literature
Intellectual disability v3.1561 CDK9 Konstantinos Varvagiannis gene: CDK9 was added
gene: CDK9 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 26633546; 30237576; 29302074; 33640901
Phenotypes for gene: CDK9 were set to Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures
Penetrance for gene: CDK9 were set to Complete
Review for gene: CDK9 was set to GREEN
Added comment: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent.

CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4].

Animal models also provide some supporting evidence [discussed Ref4].

Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below.

[1]-----
Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity.

After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing.

Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630).

Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect.

Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype.

[2]-----
Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys.

All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3.

[3]-----
Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID.

In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal.

All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect.

The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2.

In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas).

[4]-----
Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia.

Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect.

In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2).

The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824).
Sources: Literature
Intellectual disability v3.1561 TAB2 Andrea Haworth reviewed gene: TAB2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 34741306; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1561 GLRA2 Konstantinos Varvagiannis reviewed gene: GLRA2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20531469, 20479760, 26370147, 28588452, 35294868; Phenotypes: Global developmental delay, Intellectual disability, Autism, Behavioral abnormality, Seizures, Microcephaly, Abnormality of eye movement; 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 v3.1561 HESX1 Arina Puzriakova Phenotypes for gene: HESX1 were changed from Septooptic dysplasia, 182230Pituitary hormone deficiency, combined, 5, 182230Growth hormone deficiency with pituitary anomalies, 182230; HESX1-RELATED COMBINED PITUITARY HORMONE DEFICIENCY to Growth hormone deficiency with pituitary anomalies, OMIM:182230; Pituitary hormone deficiency, combined, 5, OMIM:182230; Septooptic dysplasia, OMIM:182230
Intellectual disability v3.1560 FH Arina Puzriakova Phenotypes for gene: FH were changed from Fumarase deficiency, 606812Leiomyomatosis and renal cell cancer, 150800; FUMARASE DEFICIENCY to Fumarase deficiency, OMIM:606812
Intellectual disability v3.1559 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450 to Optic atrophy 12, OMIM:618977; Spinocerebellar ataxia 28, OMIM:610246; Spastic ataxia 5, autosomal recessive, OMIM:614487
Intellectual disability v3.1558 PRSS12 Zornitza Stark reviewed gene: PRSS12: Rating: AMBER; Mode of pathogenicity: None; Publications: 12459588; Phenotypes: Intellectual disability, PRSS12 related MIM#249500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1558 SLC35B2 Konstantinos Varvagiannis gene: SLC35B2 was added
gene: SLC35B2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35B2 were set to 35325049
Phenotypes for gene: SLC35B2 were set to Abnormality of the skeletal system; Short long bone; Short stature; Abnormality of epiphysis morphology; Scoliosis; Multiple joint dislocation; Global develpmental delay; Intellectual disability; CNS hypomyelination; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of the amniotic fluid
Penetrance for gene: SLC35B2 were set to Complete
Review for gene: SLC35B2 was set to AMBER
Added comment: 2 unrelated individuals with biallelic SLC35B2 variants have been reported. DD and ID were part of the phenotype.

There is currently no associated phenotype in OMIM/G2P/SysID. The gene has amber rating in the leukodystrophies panel of PanelApp Australia.

Consider inclusion in the current panel (or other possibly relevant ones eg. for skeletal disorders, short stature, white matter disorders, corpus callosum, etc) with amber rating.

---

Guasto et al (2022 - PMID:35325049) report 2 unrelated individuals with biallelic SLC35B2 variants.

SLC35B2 encodes solute carrier family 35 (3'-phosphoadenosine 5'-phosphosulfate (PAPS) transporter), member B2.

The protein is located in the Golgi membrane and serves as transporter of the activated nucleotide sulfate PAPS from the cytosol, where it is synthesized to the Golgi lumen. Another PAPS transporter is encoded by SLC35B3. In the Golgi apparatus PAPS serves as substrate of sulfotransferases for the addition sulfate to the covalently attached GAG chains of proteoglycans (PGs).

The phenotype corresponded to a chondrodysplasia manifesting as severe pre- and postnatal growth retardation (height <-4 SD and -8 SD), early scoliosis, multiple joint dislocations (in one). There was severe DD affecting motor and expressive language development with associated ID. Brain imaging was suggestive of hypomyelinating leukodystrophy with thin corpus callosum and cerebral atrophy. One individual had a cleft palate in the context of Pierre Robin sequence.

Both individuals were investigated with exome sequencing.

The first individual - born to consanguineous parents - was homozygous for an in-frame del (NM_178148.3:c.1218_1220del, p.Leu407del) with Sanger sequencing confirming the variants, and heterozygosity in parents and 2 unaffected sibs. There was an initially identified hmz CUL7 variant (for 3M syndrome), which was not felt sufficient to explain the severity of the phenotype and notably ID.

The 2nd proband was homozygous for a fs variant (c.1224_1225delAG / p.Arg408SerfsTer18 - leading to loss of the last 8 amino acids) occurring in the context of uniparental isodisomy [iUPD(6)] spanning the complete chr6 based on the exome data.

Among the evidence presented for SLC35B2 and the variants :
- SLC35B2 has high mRNA expression in fetal and adult mouse brain and other tissues.
- Upon qPCR analysis of mRNA expression in human brain samples, the gene had expression across the brain (frontal lobe grey matter, subcortical frontal white matter/cerebellum).
- High expression was shown upon analysis of mouse brain single cell RNA data (EMBL) in oligodendrocytes and microglial cells.
- RT-PCR on mRNA from skin fibroblasts (both individuals) revealed significant decrease of SCL35B2 mRNA levels compared to controls.
- Transfection of C-terminal c-myc tagged wt or mutant proteins in HEK293F cells, followed by western blotting did not reveal significant difference at the protein level. Wt SLC35B2 localized at the Golgi apparatus as suggested by colocalization with GM130 marker. The 2 variants however displayed only partial colocalization (/loss of localization specificity) with diffuse signal in the cell.
- Chondroitin sulfate disaccharide sulfation was decreased upon HPLC disaccharide analysis in patient fibroblasts and bikunin (a circulating proteoglycan in blood) electrophoretic pattern in patient sera.
- Disorders due to variants in genes implicated in proteoglycan biogenesis (e.g. XYLT1, B3GALT6, CHSY1) are associated with skeletal/connective tissue manifestations with DD/ID.
- C-elegans model lacking pst-1 (SLC35B2 ortholog) provides support that the protein is required for migration, axonal guidance, and presynaptic development in a subset of neurons.
- dsm-1 - the rat ortholog - is expressed in rat brain in D-serine and NMDA receptor rich regions. When expressed in Xenopus oocytes it accelerated the efflux of D-serine (a co-agonist for NMDA receptor).
- Variants in other members of SLC superfamily (e.g. SLC17A5, SLC35A3, SLC29A3, SLC35A2) have been associated with brain-bone phenotypes.
Sources: Literature
Intellectual disability v3.1558 CACNA2D1 Sarah Leigh Publications for gene: CACNA2D1 were set to 35293990; 28097321
Intellectual disability v3.1557 CACNA2D1 Sarah Leigh Tag Q2_22_rating tag was added to gene: CACNA2D1.
Intellectual disability v3.1557 CACNA2D1 Sarah Leigh Classified gene: CACNA2D1 as Amber List (moderate evidence)
Intellectual disability v3.1557 CACNA2D1 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 v3.1557 CACNA2D1 Sarah Leigh Gene: cacna2d1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1556 CACNA2D1 Sarah Leigh reviewed gene: CACNA2D1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1556 FBXW7 Konstantinos Varvagiannis gene: FBXW7 was added
gene: FBXW7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW7 were set to 33057194; 35395208; 30885698; 26482194; 19963109; 20332316
Phenotypes for gene: FBXW7 were set to Neurodevelopmental abnormality; Global developmental delay; Intellectual disability; Macrocephaly; Microcephaly; Abnormality of brain morphology; Abnormality of the corpus callosum; Abnormality of the cerebellum; Abnormality of the cardiovascular system; Seizures; Strabismus; Abnormality of the palate
Penetrance for gene: FBXW7 were set to unknown
Review for gene: FBXW7 was set to AMBER
Added comment: While Kaplanis et al (2020 - Ref1), identified FBXW7 among 285 genes significantly associated with developmental disorders, a recent study by Stephenson et al (2022 - Ref2) describes the neurodevelopmental phenotype of 35 individuals making this gene relevant to the current panel. There are previous reports of dn/inh germline variants in individuals (likely 7) with tumor predisposition although a neurodevelopmental phenotype was not reported in most cases.

There is currently no FBXW7-related phenotype in OMIM.

The gene is included in the DD panel of G2P [associated with: FBXW7-related developmental disorder (monoallelic), confidence: definitive, citing the study by Kaplanis et al]. SysID lists FBXW7 among the candidate ID genes (same Ref.). The gene has a green rating for ID in PanelApp Australia (VCGS participating in the recent publication).

Consider inclusion with amber/green rating. Also consider inclusion in other panels that may be relevant(macro/microcephaly, seizures, CHD, corpus callosum / cerebellar abnormalities, cleft palate, WT, etc).

[1]------------
Kaplanis et al (2020 - PMID: 33057194), by combining exome data from 31,058 parent offspring trios from the DDD study, Radboudumc and GeneDx, identified 285 genes significantly associated with developmental disorders, 28 of which (incl. FBXW7) not previously robustly associated with these disorders.

[2]------------
Stephenson et al (2022 - PMID: 35395208) provide clinical information on 35 individuals harboring germline monoallelic FBXW7 variants or chromosomal deletions spanning this gene.

The phenotype corresponded to a phenotypically variable NDD characterized by hypotonia (in about 2/3), neurodevelopmental abnormality (34/35 - as discussed later), seizures (8/35), abnormal brain morphology (13/17 - in 7/17 abnormal CC, in 5/17 abn. cerebellum, etc), head circumference (macrocephaly in 10/35, microcephaly in 2/35). Additional features included abnormal palate or uvula morphology (10/35 - cleft palate in 3 from 2 families while 1 individual from a 3rd family had bifid uvula) or abnormal heart morphology (11/35), ophthalmologic features (e.g. strabismus in 5/35) or hearing impairment (2/35). There was no recognizable gestalt (deeply set eyes with upper eyelid fullness in 9/35).

As for the DD/ID this ranged from borderline to severe, characterized as mild-moderate in 27/35, severe in 3/35. One individual did not present neurodevelopmental abnormality 1/35.

FBXW7 encodes F-box and WD40 domain protein 7 which is part of the SCF E3 ligase complex (SKP1/CUL1/F-box protein) exerting a role of recognition and binding of target proteins for degradation by the ubiquitin proteasome system. In this way FBWX7 participates in regulating a network of proteins involved in cell division, growth, differentiation (as summarized by Roversi et al - Ref2).

Most individuals were investigated by trio-WES/WGS (few with singleton WES or CMA only). 28 germline FBXW7 variants were identified incl. missense (N=21), pLoF (predicted or not to undergo NMD) and 2 deletions encompassing but not limited to FBXW7.

Additional SNVs/CNVs (e.g. an inh intragenic DPP6 dup in one individual (#9) with deletion, other de novo 4q CNVs (#10), an inh 22q spanning partially an ISCA TS region, a CACNA1A and KMT2D SNV, etc) were reported in few individuals.

Most variants arose dn (N=30) with two individuals displaying mosaicism (2/30) and three individuals having inherited the variant from their affected parent. CNVs had occurred dn.

3 missense SNVs were recurrent in unrelated individuals.

All variants identified affected all FBXW7 isoforms.

As the authors comment missense variants clustered at the C-terminal half of the protein with most (16/21) occurring within the WD40 domain. [The N-terminal part commented in the literature to affect localization].

The crystal structure of FBXW7 and SKP1 complex has been determined with CYCLIN E1/DISC1 as substrates, and in silico modeling revealed that all missense variants aligned with residues required for this interaction, or adjacent ones.

All were absent from gnomAD, while missense variants from gnomAD (N=78) were not predicted have significant effect on the binding affinity.

Variant studies revealed that most missense variants (6/7 tested - Arg689Gln being the exception) are unlikely to cause protein instability or degradation in vivo.

Co-expression of these missense variants with CYCLIN E1 / E2, known FBXW7 substrates revealed that variants were less efficient at degrading the substrate with variants in the WD40 domain having greater impact (in some cases E1 / E2 - specific).

Elav-Gal4 mediated neuronal knockdown of the Drosophila ortholog archipelago (ago) using 2 RNAi-s with different efficiency was shown to affect learning or compromise neuronal function (also related to the level of knockdown).

The authors summarize results from animal models for the role of this gene in development and the nervous system.

KO mice die in utero at E10.5 manifesting abn. of hematopoietic or vascular development and heart-chamber maturation(*). Some htz knock-in for human cancer variants, display perinatal lethality, abn lung, cleft palate (30%)(*),etc. Conditional gut specific deletion results in impaired differentiation of intestinal goblet cells (*)(constipation in 16/35 in cohort). KO limited to CNS and PNS results in defective sucking and morphological brain abnormalities. Haploinsufficiency in the nervous system was associated with impaired differentiation of neural stem cells (possibly through a Notch-mediated mechanism). KO in Schwann cells of the peripheral nervous system resulted in enhanced myelination.

Excessive oligodendrocyte cells and hypermyelination (as a result of elevated Notch & mTOR signaling) are observed in homozygous mutant zebrafish or after morpholino-mediated fbxw7 knockdown.

Overall, the authors propose haploinsufficiency or loss-of-function as the underlying mechanism.

Finally, as the authors comment, FBXW7 is a tumor suppressor among the most commonly mutated genes in human cancer (3.5%). Germline variants have been previously reported in individuals with cancer (Wilms tumor, rhabdoid, etc - most summarized below). However, none of the 35 individuals in this cohort (oldest 44 y.o.) had any history of cancer.

Reports of individuals with germline variants causing (monoallelic) disruption of FBXW7 - cases without DD/ID:

[3]------------
Mahamdallie et al (2019 - PMID: 30885698) investigated with WES a cohort of 890 individuals with Wilms tumor (799 non-familial disease, 91 from WT pedigrees). In this context they identified 4 individuals having developed WT (ages: 28-76m) with FBXW7 dn or inherited LoF variants (710G>A / p.Trp237* dn - 1972C>T / p.Arg658* - inh:NA, 1017_1021del5, 670C>T - paternal / p.Arg224* inh:NA - RefSeq not provided). One additional individual with a missense variant (1753A>T / p.Ser585Cys - dn) had developed rhabdoid tumor. While the authors mentioned additional features for other subjects in their cohort, among the 5 individuals with FBXW7 variants, only one had hypotonia (ID_0592) and another (ID_7520) had two febrile convulsions.

[4]------------
Roversi et al (2015 - PMID: 26482194) described the phenotype of a 34 y.o. female with syndromic presentation (macrocephaly, nephrotic syndrome due to FSGS, Hodgkin's lymphoma, Wilms tumor, ovarian cystadenoma, breast carcinoma) harboring a 157 kb deletion of 4q31.3.

Eventual DD/ID was not reported despite detailed clinical description.

The deletion spanned almost the entire FBXW7 gene and a pseudogene (hg19 - chr4:153205202-153362047). The authors provided evidence that the del affected the maternal allele as dn event (maternal mosaicism excluded). Expression of FBXW7 in patient-derived EBV lymphoblastoid cell line revealed decreased levels of expression compared to controls. At somatic level, the authors looked for eventual 2nd hit in tumor tissue (which was not the case) while they demonstrated decreased FBXW7 expression in a WT sample compared to normal renal tissue. Previously, variants in other genes candidate for the phenotype were ruled out (Sanger & MLPA for TP53, BRCA1/2, PALB2, WT1, 11p15 MS-MLPA, std karyotype).

[5]------------
Kuiper et al (2015 - PMID: 19963109), in a 58 y.o. patient with recurrence of RCC, identified a constitutional translocation [t(3;4)(q21;q31)]. Using long-range PCR they defined the breakpoints at 3q21.3 (128379059 - hg18) between the PLXNA1 and C3orf56 genes while the chr4 breakpoint was located within the second intron of FBXW7 (pos. 153500813 - hg18). There were no additional phenotypes reported.

[6]------------
Williams et al (2010 - PMID: 20332316) reported a patient with WT harboring germline variants in WT1 and FBXW7. While the phenotype was sufficiently explained by a germline stopgain WT1 variant with a frameshift WT1 variant (as 2nd hit) confined to the tumor, the authors identified a germline in-frame FBXW7 insertion in the same individual (c.45_46insCCT / p.Thr15_Gly16insPro - RefS : NA) [if correct corresponding to: https://gnomad.broadinstitute.org/variant/4-153332910-C-CAGG - 345/281696 alleles in gnomAD].
Sources: Literature
Intellectual disability v3.1556 DTYMK Sarah Leigh Classified gene: DTYMK as Amber List (moderate evidence)
Intellectual disability v3.1556 DTYMK 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 v3.1556 DTYMK Sarah Leigh Gene: dtymk has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1555 DTYMK Sarah Leigh Tag Q2_22_rating tag was added to gene: DTYMK.
Intellectual disability v3.1555 DTYMK Sarah Leigh reviewed gene: DTYMK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1555 DTYMK Sarah Leigh Phenotypes for gene: DTYMK were changed from 31271740; 34918187; 35346037 to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Intellectual disability v3.1554 DTYMK Sarah Leigh Publications for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Intellectual disability v3.1553 MSX1 Arina Puzriakova Phenotypes for gene: MSX1 were changed from Tooth agenesis, selective, 1, with or without orofacial cleft, 106600; Orofacial cleft 5, 608874; Ectodermal dysplasia 3, Witkop type, 189500 to Ectodermal dysplasia 3, Witkop type, OMIM:189500; Orofacial cleft 5, OMIM:608874; Tooth agenesis, selective, 1, with or without orofacial cleft, OMIM:106600
Intellectual disability v3.1552 IHH Arina Puzriakova Phenotypes for gene: IHH were changed from Acrocapitofemoral dysplasia, 607778; Brachydactyly, type A1, 112500 to Acrocapitofemoral dysplasia, OMIM:607778; Brachydactyly, type A1, OMIM:112500
Intellectual disability v3.1551 HSPD1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: HSPD1.
Intellectual disability v3.1551 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant, 605280Leukodystrophy, hypomyelinating, 4, 612233; SPASTIC PARAPLEGIA AUTOSOMAL DOMINANT TYPE 13 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Intellectual disability v3.1550 HSPD1 Arina Puzriakova Publications for gene: HSPD1 were set to
Intellectual disability v3.1549 HSPD1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'both mono- and biallelic' to 'biallelic' only at the next GMS panel update. Biallelic variants cause a paediatric-onset leukodystrophy (MIM# 612233) which can feature severe DD/ID in some cases (PMID: 18571143, 27405012), whereas monoallelic variants are associated with a pure adult-onset HSP (SPG13, MIM# 605280) which is not pertinent to this panel.
Intellectual disability v3.1549 HSPD1 Arina Puzriakova Mode of inheritance for gene: HSPD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1548 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Muscular dystrophy with epidermolysis bullosa simplex, 226670; Epidermolysis bullosa simplex, Ogna type, 131950; Epidermolysis bullosa simplex with pyloric atresia, 612138; Muscular dystrophy, limb-girdle, type 2Q, 613723 to Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive, OMIM:616487; Epidermolysis bullosa simplex 5A, Ogna type, OMIM:131950; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670; Epidermolysis bullosa simplex 5C, with pyloric atresia, OMIM:612138; Muscular dystrophy, limb-girdle, autosomal recessive 17, OMIM:613723
Intellectual disability v3.1547 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from Dyskeratosis congenita, autosomal recessive 6, 616353 to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353
Intellectual disability v3.1546 CLIC2 Sarah Leigh reviewed gene: CLIC2: Rating: RED; Mode of pathogenicity: None; Publications: 28333917, 31349857, 22814392; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1546 AFF3 Arina Puzriakova commented on gene: AFF3
Intellectual disability v3.1546 AFF3 Arina Puzriakova Tag watchlist was removed from gene: AFF3.
Intellectual disability v3.1546 AFF3 Arina Puzriakova Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733; 21677750; 25660031; 31388108
Intellectual disability v3.1545 AFF3 Arina Puzriakova Phenotypes for gene: AFF3 were changed from Intellectual disability; Seizures to KINSSHIP syndrome, OMIM:619297
Intellectual disability v3.1544 DTYMK Konstantinos Varvagiannis gene: DTYMK was added
gene: DTYMK was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DTYMK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Phenotypes for gene: DTYMK were set to 31271740; 34918187; 35346037
Penetrance for gene: DTYMK were set to Complete
Review for gene: DTYMK was set to GREEN
Added comment: 4 individuals (from 3 families) harboring biallelic DTYMK pathogenic variants have been reported.

Consider inclusion in the current panel with green rating given consistent and relevant phenotype and evidence provided to date [effect of variants (LoF), pathogenesis, similar phenotypes in zebrafish model, etc].

Relevant studies are summarized below.
----
Lam et al (2019 - PMID: 31271740) described two siblings aged 25m and 7y, harboring biallelic DTYMK variants.

The phenotype consisted of hypotonia, congenital microcephaly, DD, severe ID. Other shared features included raised serum lactate, pyruvate and alanine. The phenotype was more pronounced in the younger one (epilepticus during febrile illness, epilepsy on multiple anti-convulsants, evidence of regression, etc). Brain MRI revealed marked cerebral atrophy among the findings while a lactate peak was present in spectroscopy. The elder brother developed an episode of sudden onset coma with respiratory failure at the age of 7y.

Quartet WES identified compound heterozygosity for a fs and a missense DTYMK variant (NM_012145.3:c.287_320del / p.Asp96Valfs*8 - c.295G>A / p.Ala99Thr). There were no additional findings. Previous genetic panel analysis for epilepsy was unremarkable for the 1st sib.

There are two pathways for synthesis of dNTPs, the de novo pathway operating in the cytosol only and the salvage operating in both cytosol and mitochondria. DTYMK encodes (deoxy)thymidylate kinase which catalyzes conversion (phosphorylation) of dTMP to dTDP - a step right after convergence of both pathways - in the dTTP synthesis pathway.

Mutations in TK2, an enzyme phosphorylating thymidine in mitochondria to dTMP have been associated with mitochondrial DNA depletion syndrome (MDDS).

Given this and as the 2 sibs had raised serum lactate and pyruvate, the authors performed in silico analyses to calculate mtDNA/nDNA ratio dividing the respective read depths for mitochondrial and nuclear DNA obtained from WGS data of the two sibs (blood).

This ratio was shown to be reduced in the more severely affected sib (65.5% of control) although this was not the case for the mildly affected brother (114.6%). As a control a non-MDDS mitochondrial cytopathy sample (corresponding to m.8993T>G) was used. The respective ratio which was calculated for a known POLG-related MDDS case was 15.6%.
----
Vanoevelen et al (2022 - PMID: 34918187) describe two unrelated children with hypotonia, absence of developmental progress, microcephaly, seizures (recurrent febrile seizures/myoclonic jerks). Severe cerebral atrophy (with unaffected cerebellum) was observed upon brain imaging. Other findings included puffy body/extremities. Both had complications following respiratory illness leading to demise. CNS pathology in the 1st individual revealed massive neuronal dropout, with sparing of dentate nucleus and brainstem.

CMA in both cases was normal. This was also the case for extensive metabolic investigations (which provided no evidence of eventual mitochondrial dysfunction).

WES revealed compound heterozygosity for 2 missense variants in the first individual (NM_012145.3:c.382G>A - p.Asp128Asn and c.242C>T - p.Pro81Leu). The second individual, born to consanguineous parents, was homozygous for c.242C>T / p.Pro81Leu.

In silico predictions varied although each variant were (mostly) suggestive of a deleterious effect.

Variants were both ultrarare without homozygotes in ExAC,.

The authors generated a dtymk ko zebrafish model (hmz for a frameshift variant). Zebrafish exhibited markedly smaller eyes and pericardiac edema (3dpf-), twitching movements somewhat reminiscent of epilepsy (at 3dpf), prominent edema of brain and intestine. Head size was significantly smaller at a timepoint prior to brain edema (also after correction for length). Histology provided evidence of empty spaces in brain, suggestive of neurodegeneration, with high amounts of apoptotic cells.

dTMPK activity was measured in zebrafish (at 5dpf) as well as in fibroblasts from one individual and in both cases, it was barely detectable and significantly lower compared to wt/htz zebrafish or to the activity in fibroblasts from the parents of the individual tested.

In fibroblasts from the same individual with comparison to his parents, the authors demonstrated that DNA replication was impaired (using pulse-EdU staining to quantify cells in S-phase).

Assessment of cell proliferation in the brain of dtymk ko zebrafish using phospo-Ser10-Histone H3 (pH3) staining was suggestive of severe proliferation defects in forebrain.

Impaired biosynthesis of nucleotides for DNA synthesis/repair would be predicted to result in nucleotide pool imbalance, leading to incorporation of ribonucleotides in genomic DNA with - in turn - impairment of DNA replication and genomic instability (sensitivity to strand breakage).

In line with this, genomic DNA of ko zebrafish following alkaline hydrolysis and alkaline gel electrophoresis was shown to migrate at lower position and to be more fragmented indicating increased sensitivity (due to incorporation of ribonucleotides).

Visualization of DNA breakage by γH2AX staining, following UV-irradiation of zebrafish embryos revealed persistence of elevated γH2AX levels and DNA damage response signaling, interpreted as increase in unrepaired DNA breaks.

mtDNA copy numbers in fibroblasts from the affected individual was somewhat but not significantly lower compared to his parents. Importantly, the copy numbers were similar to controls (N=5) which overall does not support mtDNA depletion as a consequence of DTYMK deficiency.

Integrity of mtDNA did not appear to be compromised , with the mitochondrial genome migrating at the expected length of 16,5 kb with no indications of mtDNA deletions for both affected individual and his parents.

Activity of the mitochondrial respiratory complexes I-V in fibroblasts from the affected individual was comparable to that of his parents.

Overall, there was no evidence for mtDNA depletion (although not studied in muscle biopsy) while functional studies failed to demonstrate mitochondrial dysfunction.

The authors discuss other disorders of impaired dTTP metabolism due to mutations in TYMP, RRM2B or CAD.
------
In a recent study using zebrafish model, Hu Frisk et al (2022 - PMID: 35346037) further demonstrate that Dtymk is essential for neurodevelopment providing evidence for expression of a compensatory thymidylate kinase-like enzyme at later stages of development (explaining survival of ko dtymk zebrafish despite the central role of this enzyme in dTTP generation). [Not further reviewed]
Sources: Literature
Intellectual disability v3.1544 KDM5B Arina Puzriakova Phenotypes for gene: KDM5B were changed from neurodevelopment delay and autism spectrum disorder; Mental retardation, autosomal recessive 65, 618109 to Intellectual developmental disorder, autosomal recessive 65, OMIM:618109
Intellectual disability v3.1543 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Gene2Phenotype confirmed gene with ID HPO; Insulin-like growth factor I, resistance to, 270450; developmental delay to Insulin-like growth factor I, resistance to, OMIM:270450
Intellectual disability v3.1542 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD), 613926; Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR), 613925 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926
Intellectual disability v3.1541 NAPB Arina Puzriakova Entity copied from Genetic epilepsy syndromes v2.506
Intellectual disability v3.1541 NAPB Arina Puzriakova gene: NAPB was added
gene: NAPB was added to Intellectual disability. Sources: Expert Review Amber,NHS GMS
Q2_22_rating, Q2_22_NHS_review tags were added to gene: NAPB.
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 28097321; 33189936; 26235277; 21040848
Phenotypes for gene: NAPB were set to Early infantile epileptic encephalopathy
Penetrance for gene: NAPB were set to unknown
Intellectual disability v3.1540 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from Feeding difficulties; Failure to thrive; Global developmental delay; Developmental regression; Intellectual disability; Seizures; Microcephaly; Cerebral atrophy; Abnormality of the corpus callosum; Vomiting; Chronic diarrhea; Gastrointestinal hemorrhage; Abnormal immunoglobulin level; Osteopenia; Abnormality of metabolism/homeostasis to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Intellectual disability v3.1539 RAC3 Arina Puzriakova Phenotypes for gene: RAC3 were changed from Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, 618577; Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, OMIM:618577
Intellectual disability v3.1538 GDAP1 Arina Puzriakova Mode of inheritance for gene: GDAP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.1537 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot-Marie-Tooth disease, type 4A, 214400; Charcot-Marie-Tooth; disease, axonal, with vocal cord paresis, 607706; Charcot-Marie-Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth disease, recessive; intermediate, A, 608340 to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Intellectual disability v3.1536 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Gene2Phenotype confirmed gene with ID HPO to Fanconi anemia, complementation group J, OMIM:609054
Intellectual disability v3.1535 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1: FANCD1 OMIM: 605724 to Fanconi anemia, complementation group D1, OMIM:605724
Intellectual disability v3.1534 ZBTB7A Konstantinos Varvagiannis gene: ZBTB7A was added
gene: ZBTB7A was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: ZBTB7A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZBTB7A were set to 31645653; 34515416
Phenotypes for gene: ZBTB7A were set to Global developmental delay; Intellectual disability; Macrocephaly; Abnormality of the lymphatic system; Sleep apnea; Increased body weight; Autism; Persistence of hemoglobin F; Abnormal leukocyte count; Recurrent infections; Umbilical hernia
Penetrance for gene: ZBTB7A were set to unknown
Review for gene: ZBTB7A was set to AMBER
Added comment: Monoallelic pathogenic ZBTB7A variants cause Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (#619769).
----
Ohishi et al (2020 - PMID: 31645653) described the phenotype of a 6y5m-old male harboring a heterozygous, de novo ZBTB7A missense variant. Features included macrocephaly, mild intellectual disability (tIQ 65) and sleep apnea. Available hemoglobin levels (in the 1st month) supported high Hb and HbF levels. Other features included PDA and an umbilical hernia.

Initial investigations incl. karyotype and CMA were normal.

The ZBTB7A variant (NM_015898.3:c.1152C>G / p.Cys384Tyr) was identified following trio WES with a list of additional findings (in suppl.) not explaining the phenotype. This SNV, confirmed by Sanger sequencing, was absent from public db with several in silico predictions in favor of a deleterious effect.

ZBTB7A on 19p encodes zinc finger- and BTB domain-containing protein 7 (or Pokemon).

The authors performed a review of 19p13.3 microdeletion cases supporting a minimum region of overlap spanning PIAS4, ZBTB7A and MAP2K2 and common features of DD and ID, macrocephaly with prominent forehead, sleep apnea. The authors argue that loss of ZBTB7A explains part of - but probably not all - features of 19p13.3 microdeletions.

ZBTB7A is known to repress expression of HBG1 and HBG2 (γ-globin), with the few available HbF patient measurements in line with this role.

Based on the structure of the protein, Cys384 (along with 3 other residues) forms a coordinate bond with the Zn+2 ion, this bond predicted to be disrupted by Tyr. Further they favor a dominant negative effect given that ZBTB7A protein is known to form dimer via interaction at the BTB domain [hetero (variant+wt) and homodimers (variant+variant) having compromised function]. To support this notion, 3 previously reported somatic variants within the zinc-finger domain have been shown to exert a dominant-negative effect (PMID cited: 26455326).
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In a collaborative study, von der Lippe et al (2022 - PMID: 34515416) identified 12 additional individuals (from 10 families) harboring monoallelic ZBTB7A missense/pLoF variants most commonly as de novo events.

The authors describe a consistent phenotype with motor (9/11) and speech delay (9/12), cognitive impairment/ID (12/12 - commonly mild, ranged from specific learning difficulties to severe ID), macrocephaly (>90%le in 11/12, >97% in 7/12), lymphoid hypertrophy of pharyngeal tissue/adenoid overgrowth (12/12), sleep apnea (9/12). Autistic features were observed in 7/12. Other phenotypes included frequent upper airway infections (10/11), weight above 97th percentile (7/11). HbF levels were elevated in 4/5 individuals with available measurements (range: 2.2% to 11.2% - ref. for subjects above 6m of age : <2% ). Other hematological issues were observed in few individuals (abn. monocyte/neutrophil counts in 3-4). Cardiovascular issues were reported in 4 (2 fam). 3 subjects had umbilical hernia. There was no common dysmorphic feature.

Various initial investigations were normal or did not appear to explain the NDD phenotype and incl. standard karyotype, CMA, targeted testing for genes/disorders previously considered (PTEN, FMR1, NSD1, BWS and PWS methylation studies, CFTR, etc). One male had a maternally inherited chrX dup not thought to explain his complex phenotype, while another had a concurrent diagnosis of thalassemia.

Individuals were investigated with singleton (or trio) WES. Of note some individuals were DDD study participants.

8 had de novo ZBTB7A variants, incl. one who harbored 2 de novo missense SNVs several residues apart. 2 sibs had inherited a fs variant from their affected parent. For the latter as well as for another subject parental samples were unavailable.

There were no other variants of interest upon exome analysis.

5 different missense, 2 nonsense and 3 fs variants were identified with pLoF all predicted to lead to NMD.

All variants were absent from gnomAD (pLI of 0.96, LOEUF 0.33 and missense Z-score of 4.04) which lists one individual with htz LoF, likely not an artifact.

Given this individual (and the familial case) the authors discuss on the mild phenotype and/or eventual reduced penetrance or underdiagnosis of the disorder.

There was no difference in severity between those with missense/truncating variants.

ZBTB7A transcription factor (or pokemon or lymphoma/leukemia-related factor) is widely expressed. It is involved in several activities being among others required to block Notch signaling which in turn drives T-cell at the expense of B-cell development. Notch pathway activation has been demonstrated in Zbtba7 ko mouse models. Finally, the authors discuss the role of notch signaling in thymus and the nervous system, as well as that ZBTB7A up/down-regulation known to repress/increase respectively HbF expression (several refs in text).
----
MGI (1335091) for Zbtb7a : "Mice homozygous for a knock-out allele die around E16.5 due to anemia and exhibit a cell autonomous defect in early B cell development". (Phenotypes from nervous system not commented on).
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Apart from OMIM (#619769), ZBTB7A is included in the DD panel of G2P (ZBTB7A-associated developmental disorder / monoallelic_autosomal / absent gene product / confidence limited) as well as among the primary ID genes in SysID. In PanelApp Australia the gene is incl. with green rating in the ID and Macrocephaly gene panels.
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Consider inclusion with amber or green rating (several individuals/families/variants, highly consistent phenotype, overlap with 19p microdeletions || variant effect not studied, animal models supporting contribution of the gene to the phenotype though no data on associated NDD ones).

Please also consider inclusion in other relevant panels (macrocephaly, lymphatic disorders, ASD, etc).
Sources: Literature, Other
Intellectual disability v3.1534 ATP2B1 Konstantinos Varvagiannis gene: ATP2B1 was added
gene: ATP2B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B1 were set to 35358416; 35358416
Phenotypes for gene: ATP2B1 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck
Penetrance for gene: ATP2B1 were set to unknown
Review for gene: ATP2B1 was set to GREEN
Added comment: Monoallelic missense/pLoF ATP2B1 variants have been reported in 12 unrelated individuals with DD/ID making this gene relevant to the current panel.

Currently there is no associated phenotype in OMIM, G2P, SysID, PanelApp Australia.

Based also on the evidence discussed below, please consider inclusion with green (rather than amber) rating.
---
Rahimi et al (2022 - PMID: 35358416) describe 12 unrelated individuals with monoallelic ATP2B1 variants.

Phenotype consisted of DD (12/12), ID [9/12 - mild or less commonly moderate, with 3 additional subjects "unclassified" likely due to their age (#6: 3y nonverbal/nonambulatory, could sit and roll / #8: 3y, sitting at 1y, 1st words:26m / #12: at 5y nonambulatory/nonverbal)]. Behavioral issues were observed in 8/11 (ASD in 5/11). Seizures were reported in 5/12 (one further had abnormal EEG). Minor features - albeit not consistent/without recognizable gestalt - were reported in 6. Anomalies of digits and marfanoid habitus were reported in 4 and 2.

All subjects were investigated by singleton/trio exome sequencing.

Previous investigations incl. karyotype, CMA, analysis of individual genes (e.g. FMR1, ZEB2) or metabolic workup were normal for several individuals with one having a concurrent diagnosis of mosaic (20%) XXY and another harboring an additional hmz variant for a liver disorder.

9 different missense and 3 nonsense ATP2B1 variants were identified, shown to have occurred de novo in all cases where parental samples were available (9/12).

ATPase plasma membrane Ca+2 transporting 1, the protein encoded by ATP2B1, is an ATP-driven calmodulin-dependent Ca+2 pump which removes intracellular calcium from the cytosol. As the authors comment calcium pumps are thought to have a crucial role on neuronal function.

All variants identified were absent from gnomAD with the exception of c.2365C>T / p.Arg789Cys (de novo) which is present once in the database. ATP2B1 has a pLI of 1 and a missense Z-score of 5.29.

The variants affected several ATP2B1 isoforms. Variants were reported using NM_001001323.2, corresponding to ATP2B1a isoform which is mainly detected in brain (as also in GTEx).

In silico predictions were in favor of a deleterious effect and structural modeling supported the role of the affected residues.

The nonsense variants occurred in positions predicted to lead to NMD (not studied).

Transfection of an ATP2B1-yellow fluorescent protein (YFP) expression plasmid for wt or variants in HEK293 cells, revealed membranous fluorescence for wt, significantly altered localization for 3 variants (Asp239Gly, Thr264Ile, Arg991Gln), shift to cytoplasmic localization for 4 others (Thr425Lys, Arg763Pro, Glu824Lys, Gln857Arg) with statistically non-significant effect for 2 others (His459Arg and Arg789Cys).

Fluorometric [Ca+2]i analysis in HEK293 cells expressing wt or variant ATP2B1 revealed that all missense variants affected Ca+2 transport. This was not the case for wt ATP2B1 or for another missense variant used as control (drawn from gnomAD).

Of note, a further (13th) affected individual with another missense variant (c.1793T>C / p.Ile598Thr) was excluded from the phenotypic analysis. The membrane localization and Ca+2 transport did not appear to be affected by this variant which was classified as VUS although it a different impact from those studied.

Overall loss-of-function is thought to be the underlying mechanism based on the above (and supported by few reported cases with gross deletions spanning also ATP2B1). A dominant negative effect for missense variants (affecting heteromeric complex formation with neuroplastin or basigin) could not be completely excluded, but not supported either by the localization of the identified variants.

In the supplement the authors include 3 DDD study participants previously reported to harbor de novo pLoF/missense variants though with few available clinical information (PMID: 33057194 - DDD13k.05076 : c.2883del / DDD13k.04028 : c2512A>C - p.Ile838Val / DDD13k.08944 : c.2129A>C - p.Asp710Ala).

The authors discuss on the role of ATP2B1 on Ca+2 homeostasis in the CNS and neurodevelopment overall (also based on isoform expression in rat brain).
Sources: Literature
Intellectual disability v3.1534 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Intellectual disability v3.1533 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.
Intellectual disability v3.1533 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1532 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger), 614862Peroxisome biogenesis disorder 4B, 614863; ZELLWEGER SYNDROME (ZWS) to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Intellectual disability v3.1531 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
Intellectual disability v3.1530 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Intellectual disability v3.1530 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1530 MAN2C1 Konstantinos Varvagiannis gene: MAN2C1 was added
gene: MAN2C1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2C1 were set to 35045343
Phenotypes for gene: MAN2C1 were set to Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Abnormality of the corpus callosum; Ventriculomegaly; Polymicrogyria; Abnormality of the face; Macrocephaly
Penetrance for gene: MAN2C1 were set to unknown
Review for gene: MAN2C1 was set to GREEN
Added comment: Biallelic pathogenic MAN2C1 variants cause Congenital disorder of deglycosylation 2 (# 619775). Mild to moderate impairment of intellectual development is a feature in most patients as in the OMIM's clinical synopsis for this disorder.
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Specifically, Maia et al (2022 - PMID: 35045343) report the clinical features based of 6 relevant individuals (4/6 aged 4-18years and 2/6 fetuses) from 4 families. These individuals had non-specific dysmorphic features (micro/retrognathia being the most common in 5/6), different congenital anomalies, variable degrees of ID (3/4), as well as brain MRI abnormalities (PMG in 3/6 from 3 fam, ventriculomegaly in 3/6 from 2 fam, callosal anomalies in 4/6 from 3 fam, cerebellar hypoplasia 2/6 - 2 fam, vermis hypoplasia 4/6 - 3 fam etc). Macrocephaly was reported for 2/6 individuals (2 fam).

While ID was observed in 3/4 individuals of relevant age (mild in 1/4, moderate in 1/4, unk in 1/4), delayed motor and language development was reported for all (4/4).

All individuals harbored biallelic MAN2C1 variants following exome sequencing (previous investigations not reported), and Sanger sequencing was used for validation and segregation (parents/sibs).

There were no putative pathogenic variants in known disease genes.

MAN2C1 encodes mannosidase, alpha, class 2c, member 1, an enzyme playing a role in deglycosylation of free oligosaccharides (fOSs). The latter are generated and released in the cytoplasm or the ER lumen during N-glycosylation of proteins. fOSs are generated from two different pathways (ERAD and LLO) with a defect in an enzyme of the NGLY1 already described to cause a NDD due to defect of deglycosylation. In a later step oligossaccharides are trimmed by the action of ENGase to form fOS containing one GlcNAc (N-Acetylglucosamine) residue (fOSGn1) at the reducing end. Processing of these fOSs by the cytosolic α-mannosidase (MAN2C1) converts Man7-9Gn1 to Man5Gn1 subsequently transported to lysosomes for degradation.

Variants incl. 3 missense SNVs incl. c.2612G>C/p.Cys871Ser, c.2303G>A/p.Arg768Gln, c.607G>A/p.Gly203Arg, one splice variant (c.601-2A>G/p.Gly201Profs*10) and one indel (c.2733_2734del/p.His911Glnfs*67). [RefSeq NM_006715.3]

Most were present in gnomAD with low AF ranging from 0.013% to 0.11% while c.2303G>A/p.Arg768 has an AF of 0.33% with 5 homozygotes(*) in the database. Conservation and in silico predictions supported their effect.

For the variant affecting the splicing acceptor site (c.601-2A>G) studies in patient fibroblasts confirmed skipping of ex6. Fibroblasts from 2 sibs cmp htz for Arg768Gln and c.601-2A>G (Gly201Profs*10) were studied for protein levels, demonstrating 90% reduction in the amount of MAN2C1. There was no truncated protein observed upon immunoblot. Protein abundance was not affected in fibroblasts from the individual who was homozygous for Gly203Arg.

Mannosidase activities were studied upon overexpression in a HEK293 model, with Gly203Arg presenting similar activity to WT and Arg768Gln exhibiting only a tiny residual activity. Cys871Ser showed increased activity compared to WT.

Using fibroblasts from controls and the same individuals as above, the authors showed that pathogenic MAN2C1 variants caused defects in fOS processing (delayed processing of high oligomannose species, reduced production of M5Gn1 with M8 and M9Gn1/2 species remaining at high levels) supporting a total/partial loss of mannosidase activity for Arg768Gln and Gly203Arg.

In MAN2C1-KO HAP1 cell lines, M7-M9Gn1 species accumulated while M5Gn1 - the product of MAN2C1 - were absent. Complementation of KO HAP1 cells with Gly203Arg, Arg768Gln and Cys871Ser suggested impaired fOS processing for Gly203Arg and Arg768Gln (with significant amounts of M7-M9Gn1 species). Cells complemented with Cys871Ser did not exhibit fOS processing defects.

The authors speculate that Cys871Ser could affect a non-mannosidase function of the enzyme relevant to brain development or that it might lead to abnormal inter-subunit interactions or tetramer formation.

Finally, Maia et al summarize findings in previously described Man2c1-KO mice (cited PMID: 24550399). These appeared normal, did not exhibit differences in growth or lifespan and did not present behavioral alterations. Man2c1-KO mice had CNS involvement with histological analyses in favor of neuronal and glial degeneration with multiple vacuoles in deep neocortical layers and telencephalic white matter tracts. Vacuolization was not observed upon brain histology for the 2 fetuses studied which Maia et al speculate may occur at a later stage. In KO mice there was considerable accumulation of Man8–9GlcNAc oligosaccharides.
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G2P includes MAN2C1 in it's DD panel (confidence: strong, MAN2C1-associated neurodevelopmental disorder with cerebral malformations). In PanelApp Australia, this gene is rated green in the ID, polymicrogyria, cerebellar hypoplasia and fetal anomalies gene panels.

Consider inclusion in the current panel with green (3 individuals/families/variants, role of the gene, NDD phenotype also reported for NGLY1-related disorder of deglycosylation, variant studies) or amber rating (ID not a universal feature, still DD observed in all affected individuals).

Please consider adding this gene in other relevant panels (as in PanelApp Australia, also for corpus callosum abnormalities, metabolic disorders, etc).
Sources: Literature, Other
Intellectual disability v3.1530 TLK2 Arina Puzriakova Publications for gene: TLK2 were set to 27479843; https://doi.org/10.1016/j.ajhg.2018.04.014
Intellectual disability v3.1529 SLC38A3 Konstantinos Varvagiannis gene: SLC38A3 was added
gene: SLC38A3 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC38A3 were set to 34605855
Phenotypes for gene: SLC38A3 were set to Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia
Penetrance for gene: SLC38A3 were set to Complete
Review for gene: SLC38A3 was set to GREEN
Added comment: Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284).

The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7).

Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations.

In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families.

Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam).

The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs.

SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle.

While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability.

Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7).

Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways).

Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457.

There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels.

Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered).

Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc.
Sources: Literature, Other
Intellectual disability v3.1529 ALG8 Sarah Leigh Publications for gene: ALG8 were set to 0
Intellectual disability v3.1528 ADAT3 Arina Puzriakova Phenotypes for gene: ADAT3 were changed from Mental retardation, autosomal recessive 36, 615286; MRT36 to Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies, OMIM:615286
Intellectual disability v3.1527 TBXAS1 Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from Ghosal hematodiaphyseal syndrome, OMIM:231095 to Ghosal hematodiaphyseal syndrome, OMIM:231095
Intellectual disability v3.1527 TBXAS1 Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from Ghosal hematodiaphyseal syndrome, 231095; ?Thromboxane synthase; deficiency, 614158 to Ghosal hematodiaphyseal syndrome, OMIM:231095
Intellectual disability v3.1526 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar ataxia, autosomal recessive 14; MIM:615386; Developmental delay to Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Intellectual disability v3.1525 CACNA2D1 Konstantinos Varvagiannis gene: CACNA2D1 was added
gene: CACNA2D1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990; 28097321
Phenotypes for gene: CACNA2D1 were set to Abnormal muscle tone; Feeding difficulties; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of movement; Cortical visual impairment; Pain insensitivity
Penetrance for gene: CACNA2D1 were set to Complete
Review for gene: CACNA2D1 was set to GREEN
Added comment: Consider inclusion in the current panel with green rating.

Recent report of 2 unrelated individuals with DEE due to biallelic CACNA2D1 variants. Both referred to neurology/genetics for hypotonia/severe DD prior to onset of seizures.

One further individual with hypotonia and severe ID (seizures not discussed, age unknown).

Gene with established role, encoding α2δ-1 subunit of Cav channels. Studies for the variants support loss-of-function as the underlying effect.

Eventual contribution of monoallelic variants to NDD-phenotypes discussed (and put in question) in Ref [1] below.

There is currently no phenotype for CACNA2D1 in OMIM/G2P. In SysID this gene is listed among the candidates for ID, based on a previous report. CACNA2D1 is not currently included in the ID/epilepsy panels in PanelApp Australia.

See also relevant review in epilepsy panel (Dr. H. Lord).

Please consider also inclusion in other panels (e.g. microcephaly, corpus callosum, movement disorders, etc).

[1] ----
Dahimene et al (2022 - PMID: 35293990) describe the phenotype of 2 unrelated individuals with biallelic CACNA2D1 variants.

Overall, the phenotype corresponded to an early-onset DEE, characterized by abnormal muscle tone (axial hypotonia 2/2 with spasticity in extremities in 2/2), feeding difficulties (2/2), profound DD and ID (2/2), microcephaly (2/2 - approx. -2 SD in both), seizures (2/2 - 1st : onset 9m with absences and later generalized seizures, 2nd : onset 11m with hemi-clonic seizures and atypical absences). Other features included cortical visual impairment (2/2) and movement disorder (incl. choreiform movements 2/2, orofacial dyskinesia 2/2 and dystonic episodes 1/2). Brain MRI revealed corpus callosum anomalies (2/2) and cerebral atrophy (2/2). Both had echocardiography (abnormal in 1/2 - tiny PFO) and electrocardiography which was normal. Both exhibited insensibility to pain.

Presentation is relevant to the current panel as first symptoms in the first 3 months with severe hypotonia and poor head control (2/2) with evaluation in neurology/genetics preceding onset of seizures in both.

Trio ES was performed for both individuals and their (healthy) parents and revealed homozygosity for a fs variant in the first [NM_000722.3:c.818_822dup / p.(Ser275Asnfs*13)] and compound htz for a fs and a missense variant [c.13_23dup / p.(Leu9Alafs*5) and c.626G>A / p.(Gly209Asp)] in the second affected individual, respectively.

Eventual additional variants were not discussed.

Previous investigations are only provided for the 2nd and were all normal (karyotype, CMA, 15q methylation, epilepsy/neurometabolic gene panels).

Voltage-gated calcium channels are heteromultimers comprising different subunits incl. an alpha-1 (α1), α2δ (alpha-2/delta), beta (β) and gamma (γ). CACNA2D1 is one of the 4 genes (CACNA2D1-4) encoding the alpha-2/delta subunit. Its product is post-translationally processed into 2 peptides, an alpha-2 and a delta subunit, held by a disulfide bond.

Biallelic variants in CACNA2D2 - also encoding an alpha-2/delta subunit - cause cerebellar atrophy with seizures and variable developmental delay (# 618501).

Variant studies support loss-of-function effect for the studied variants, notably by NMD for the fs one, and severe impairment of the Cav2 channel function for the missense one :
- CACNA2D1 mRNA was reduced to 6-9% compared with control in fibroblasts from the 1st individual. mRNA levels for the 2nd subject were similar to control.
- Quantification of the protein in whole-cell lysates from fibroblasts revealed lower α2δ levels compared to control (10-12% and 31-38% applying to the 1st and 2nd individual).
- CACNA2D3 mRNA levels in fibroblasts from the 2nd patient were 2-7x higher compared to the 1st or controls suggesting a possible compensatory effect. CACNA2D2/4 mRNA levels were too low for quantification.
- Gly209 lies within the gabapentin and amino-acid binding pocket and this residue is invariable in CACNA2D1/CACNA2D2 in all vertebrates and paralogs.
- Transfection of tsA-201 cells with either WT or G209D HA-tagged α2δ revealed reduced cell surface expression for this missense variant (~80, for biotinylated form ~86%).
- In tsA-201 cells transfected with HA-tagged Cav2.2/β1b and either α2δ-1-WT, no α2δ-1 or α2δ-1-G209D, WT resulted in increased 13x currents with no increase applying to G209D (or in absence of α2δ). Plasma membrane expression of double (GFP/HA) tagged Cav2.2 was increased upon co-expression with WT α2δ-1 which was not the case for α2δ-1-G209D.
- In hippocampal neurons, double (GFP/HA)-tagged Cav2.2 could not be detected at the cell surface in the presence of α2δ-1-G209D (or no α2δ) in contrast with strong expression in presence of α2δ-1-WT. α2δ-1-G209D did not promote trafficking of Cav2.2 into hippocampal neurites, as indicated by reduced signals for both HA and GFP (for cell surface and total Cav2.2 respectively).
- Co-expression of double (GFP/HA) tagged Cav2.2 with β1b and either HA-α2δ-1-WT or HA-α2δ-1-G209D in tsA-201 cells, revealed reduced complex formation of G209D with Cav2.2 Co-immunoprecipitated HA-α2δ-1-G209D had higher molecular weight compared to HA-α2δ-1-WT which suggests that α2δ-1-G209D remains as the uncleaved immature form (probably in the ER).

Mouse model (several Refs in text):
Mild cardiac phenotype and reduced ventricular myocyte Ca current density was observed in hmz ko mice. Similarly to the insensibility to pain human phenotype, mice had delayed neuropathic pain-related responses. Overexpression of a2δ-1 resulted in epileptiform EEG and behavioral arrest, overall supporting a critical role of α2δ-1 for mouse brain.

The authors underscore that the parents of both patients (htz carriers) were healthy and review previous literature for association of monoallelic variants with epilepsy, ID and arrhythmogenic disorders (in suppl.) [Refs not here reviewed].

As for the NDD phenotype, CACNA2D1 is within a previously defined small region of overlap for 7q21.11 microdeletions associated with ID+/-epilepsy. The same study did not reveal de novo SNVs in any of the 3 contained genes within this SRO (HGF, CACNA2D1, PCLO) in 4293 patients with NDD [cited PMID: 28240412]. A frameshift variant (c.2625del) was identified in a 13-yo girl with infantile spasms and normal intelligence [cited PMID: 25877686]. A 1-bp insertion (c.659-2_659-1insT / not studied at the mRNA level) was identified in another 14-yo female with ID and epilepsy [cited PMID: 34356170]. The authors state that the phenotype (/differences) of these individuals as well as presence of pLoF CACNA2D1 variants in gnomAD [still pLI of 1] put in question pathogenicity of monoallelic variants for these phenotypes.

The role of heterozygous missense variants described in relation to arrhythmogenic disorders is also discussed extensively (some downgraded to LB/VUS, others having a relatively high MAF and presence of 1-2 homozygotes in gnomAD).

[2] ----
In an article cited by SysID for CACNA2D1 (2017 - PMID: 28097321), Reuter et al studied with WES and autozygosity mapping individuals with NDD belonging to consanguineous families.

As in eTables1/3, a male - single affected individual born to consanguineous parents from Turkey (MR150) - was investigated by singleton ES.

This individual was homozygous for a missense CACNA2D1 SNV [NM_000722.2:c.1514C>T;p.(Thr505Ile)].

Prior investigations are unavailable (although individuals with previously known P/LP CNVs were excluded).

The phenotype - briefly reported - included hypotonia, severe ID, stereotypic behaviors, inguinal hernia and omphalocele. Presence of seizures was not commented on. The age of this individual was not reported.
Sources: Literature, Other
Intellectual disability v3.1525 ACTL6B Arina Puzriakova Phenotypes for gene: ACTL6B were changed from Global developmental delay; Intellectual disability to Developmental and epileptic encephalopathy 76, OMIM:618468; Intellectual developmental disorder with severe speech and ambulation defects, OMIM:618470
Intellectual disability v3.1524 ACER3 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v1.227
Intellectual disability v3.1524 ACER3 Arina Puzriakova gene: ACER3 was added
gene: ACER3 was added to Intellectual disability. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: ACER3.
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 26792856; 32816236; 34281620
Phenotypes for gene: ACER3 were set to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Intellectual disability v3.1523 TRAPPC10 Konstantinos Varvagiannis reviewed gene: TRAPPC10: Rating: AMBER; Mode of pathogenicity: None; Publications: 35298461, 30167849; Phenotypes: Abnormal muscle tone, Global developmental delay, Intellectual disability, Microcephaly, Short stature, Gait disturbance; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1523 SLC12A5 Sarah Leigh reviewed gene: SLC12A5: Rating: ; Mode of pathogenicity: None; Publications: 24928908, 24668262, 26333769; Phenotypes: Developmental and epileptic encephalopathy 34, OMIM:616645; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1523 SLC12A5 Sarah Leigh Publications for gene: SLC12A5 were set to 24668262; 26333769
Intellectual disability v3.1522 SLC12A5 Sarah Leigh Tag Q1_22_MOI tag was added to gene: SLC12A5.
Intellectual disability v3.1522 SLC12A5 Sarah Leigh Phenotypes for gene: SLC12A5 were changed from FEBRILE SEIZURES to Developmental and epileptic encephalopathy 34, OMIM; 616645
Intellectual disability v3.1521 SLC12A5 Sarah Leigh Publications for gene: SLC12A5 were set to 24668262
Intellectual disability v3.1520 ZNF292 Rachel Challis reviewed gene: ZNF292: Rating: ; Mode of pathogenicity: None; Publications: PMID: 31723249; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1520 PAN2 Konstantinos Varvagiannis gene: PAN2 was added
gene: PAN2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAN2 were set to 29620724; https://doi.org/10.1038/s41431-022-01077-y
Phenotypes for gene: PAN2 were set to Global developmental delay; Intellectual disability; Sensorineural hearing impairment; Abnormality of the genitourinary system; Abnormality of the cardiovascular system; Abnormality of blood and blood-forming tissues; EEG abnormality; Seizures; Anorectal anomaly; Abnormality of the skeletal system; Abnormality of the eye; Abnormality of head or neck
Penetrance for gene: PAN2 were set to Complete
Review for gene: PAN2 was set to AMBER
Added comment: 1.
Maddirevula et al (2018 - PMID: 29620724) first reported on the phenotype associated with biallelic pathogenic variants in PAN2.

This concerned a male (15DG2222) born to consanguineous parents and exhibiting MCA, dysmorphic features and global DD (age of 34 m). Features incl. imperforate anus, metopic craniosynostosis, scoliosis, CHD (PFO, PDA, VSD), renal anomalies (duplicated collecting system) and abnormalities of the eye (posterior embryotoxon, maculopathy).

As the other 411 individuals from the cohort, the child had 1st-tier testing genetic testing using a dysmorphology/skeletal dysplasia panel of 296 genes.

Subsequent autozygome analysis (Axiom genotyping platform) was used to identify ROH (authors state "segregating within the family", in pedigree the proband was the single affected person and single child).

WES revealed a PAN2 indel. [NM_001166279.1:c.3162delC / p.(Ser1055Profs*4)].

There were no additional studies.

Role of PAN2 and animal models discussed as below.
---
2.
Reuter et al. (2022 - https://doi.org/10.1038/s41431-022-01077-y) describe the phenotype of 5 additional individuals - from 3 unrelated families (2 consanguineous) - harboring biallelic PAN2 variants. The authors review the phenotype of the previously described case.

Features included DD (6/6), ID (4/5 with relevant age in the mild-moderate range, 1/5 had borderline IF), sensorineural hearing loss (5/6) and incompletely penetrant congenital anomalies of the heart (4/6 - TOF, septal defects, Ao root dilat), urinary malformations (4/6 - hypoplasia/agenesis, anovesical fistula), ophthalmological anomalies (2/6 - Rieger, posterior embryotoxon, etc). EEG anomalies or seizures were noted in 4/6. Craniofacial feat. in >=2/6 included cleft palate/bifid uvula, ptosis, hypertelorism, abn. of the nose, low-set ears, short neck. There was no comprehensive evaluation for skeletal dysplasia despite short stature/skeletal anomalies in multiple individuals. Hematological anomalies were reported in 2, possibly explained by another concurrent diagnosis (of GSD) in one individual.

WGS was performed for 1 individual, and WES for 4 members of the 2nd family and the proband in the 3rd. ROH identified in all 3 families (1 non-consanguineous but from the same region of Italy) are mentioned in the suppl. Sanger sequencing for parents and affected/unaffected sibs was mentioned for the 2 families with solo WGS/WES. One individual had a dual - previously established - diagnosis (of SLC37A4-related GSD) not related to his NDD. There were no other candidate variants except for VUS or variants in 'genes of uncertain significance'.

The majority of mammalian mature mRNAs have polyA tails, added during RNA processing. PAN2 encodes a subunit of the Pan2-Pan3 deadenylation complex which shortens mRNA 3' polyA tails, regulating mRNA stability/translation efficiency.

Specifically Pan2 is the catalytic subunit, while the interaction with Pan3 mediates efficient mRNA binding. Deadenylation in cytoplasm is mostly carried out by the Pan2-Pan3 or Ccr4-Not compexes. While perturbations of mRNA metabolism/decay are established causes of NDD and ID. In particular, monoallelic variants in genes of Ccr4-Not complex (inc. CNOT1/2/3) already causative of NDDs.

All affected individuals were homozygous for pLoF PAN2 variants, namely (NM_001166279.2): c.2335G>T / p.(Glu779*) [Fam1], c.3408dupT / p.(Glu1137*) [Fam2], c.574-2A>G / p.? [Fam3].

Variants were absent from gnomAD (where PAN2 has a pLI:0.94, o/e:0.19).

There were no variant studies performed. The splicing variant is predicted in silico to abolish the splice-acceptor site, with in-frame skippling of ex5 which codes a repeat within the WD40 domain. Previous studies in yeast have shown that this domain is important for sensing the length of the polyA tail, with absence of this domain resulting in impaired deadenylation of 90A tails (similarly to complete Pan2 del) [cited PMID: 31104843].

Overall PAN2 loss-of-function is thought to be the underlying disease mechanism.

Partial functional redundancy of Pan2/Pan3 (initiation of deadenylation) and Ccr4-Not complexes (further shortening of polyA) is speculated to mitigate consequences of PAN2 LoF in humans.

In yeast Pan2Δ, Ccr4Δ and Pan2Δ/Ccr4Δ have been studied with more severe phenotypes in double mutants where ability to shorten mRNA polyA tails was abolished [cited PMID:11239395]. In yeast extracts lacking Pan2p and Pan3p, transcripts were polyadenylated to >90-200 adenosines [cited PMID: 9774670]

Mouse mutants (MGI:1918984) had increased heart weight, increased eosinophil cell number while homozygosity for a stopgain allele (by ENU mutagenesis) was shown to result in embyonic lethality.

Finally, given the presence of thrombocytopenia and anemia in 3 individuals (2 families) as well as the link between mRNA deadenylation and telomere disease, telomere length analyses from WGS data were performed (TelSeq/Expansion Hunter dn), but there was no evidence for telomeric shortening.
---
Currently, there is no PAN2-related phenotype in OMIM/G2P/SysID/PanelApp Australia.
---
Consider inclusion in the ID panel with amber rating [>3 individuals/families/variants, though variant studies not performed (NMD/splicing) and authors of 2nd study recognize possibility of additional/concurrent diagnoses in individuals from consanguineous families, possibility of missed dn variants due to singleton WGS/WES in 2 fam. Also the presumed deadenylation defect not studied to date].

Please consider adding this gene to other panels - eg. for sens. hearing loss (5/6 - 3 fam), urinary tract anomalies (4/6 - 4 fam), congenital (4/6 - 3fam), anorectal malformations (2/6 - 2 families, incl. fistula or imperforate anus), clefting (2/6 - 1 fam), hematological disorders, etc.

For the time being, not added in epilepsy panel as some individuals had only EEG anomalies, few had also clinical seizures not necessarily requiring treatment.
Sources: Literature
Intellectual disability v3.1520 HIST1H4C Konstantinos Varvagiannis reviewed gene: HIST1H4C: 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: 28920961, 35202563; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 1, #619758; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1520 HIST1H4J Konstantinos Varvagiannis reviewed gene: HIST1H4J: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 31804630, 35202563; Phenotypes: ?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1520 HIST1H4D Konstantinos Varvagiannis gene: HIST1H4D was added
gene: HIST1H4D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4D were set to 35202563
Phenotypes for gene: HIST1H4D were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4D were set to Complete
Mode of pathogenicity for gene: HIST1H4D 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: HIST1H4D was set to AMBER
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4E Konstantinos Varvagiannis gene: HIST1H4E was added
gene: HIST1H4E was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4E were set to 35202563
Phenotypes for gene: HIST1H4E were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4E were set to unknown
Mode of pathogenicity for gene: HIST1H4E 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: HIST1H4E was set to GREEN
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4F Konstantinos Varvagiannis gene: HIST1H4F was added
gene: HIST1H4F was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4F was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4F were set to 35202563
Phenotypes for gene: HIST1H4F were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4F were set to unknown
Mode of pathogenicity for gene: HIST1H4F 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: HIST1H4F was set to AMBER
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4I Konstantinos Varvagiannis gene: HIST1H4I was added
gene: HIST1H4I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4I was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4I were set to 35202563
Phenotypes for gene: HIST1H4I were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4I were set to unknown
Mode of pathogenicity for gene: HIST1H4I 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: HIST1H4I was set to GREEN
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 GLS Arina Puzriakova Tag for-review was removed from gene: GLS.
Tag watchlist tag was added to gene: GLS.
Intellectual disability v3.1520 ISCA-37423-Gain Arina Puzriakova commented on Region: ISCA-37423-Gain
Intellectual disability v3.1520 ISCA-37423-Loss Arina Puzriakova commented on Region: ISCA-37423-Loss
Intellectual disability v3.1520 ISCA-37441-Loss Eleanor Williams commented on Region: ISCA-37441-Loss
Intellectual disability v3.1520 ISCA-37430-Gain Arina Puzriakova commented on Region: ISCA-37430-Gain
Intellectual disability v3.1520 ISCA-37434-Loss Arina Puzriakova commented on Region: ISCA-37434-Loss
Intellectual disability v3.1520 ISCA-37440-Loss Eleanor Williams commented on Region: ISCA-37440-Loss
Intellectual disability v3.1520 ISCA-37430-Loss Arina Puzriakova commented on Region: ISCA-37430-Loss
Intellectual disability v3.1520 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Intellectual disability v3.1520 ISCA-46299-Gain Arina Puzriakova commented on Region: ISCA-46299-Gain
Intellectual disability v3.1520 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Intellectual disability v3.1520 ISCA-37494-Gain Arina Puzriakova commented on Region: ISCA-37494-Gain
Intellectual disability v3.1520 ISCA-37493-Loss Arina Puzriakova commented on Region: ISCA-37493-Loss
Intellectual disability v3.1520 ISCA-37494-Loss Arina Puzriakova commented on Region: ISCA-37494-Loss
Intellectual disability v3.1520 ISCA-37478-Gain Eleanor Williams commented on Region: ISCA-37478-Gain
Intellectual disability v3.1520 ISCA-37468-Loss Arina Puzriakova commented on Region: ISCA-37468-Loss
Intellectual disability v3.1520 ISCA-37446-Loss Eleanor Williams commented on Region: ISCA-37446-Loss
Intellectual disability v3.1520 ISCA-37433-Gain Arina Puzriakova commented on Region: ISCA-37433-Gain
Intellectual disability v3.1520 ISCA-37446-Gain Arina Puzriakova commented on Region: ISCA-37446-Gain
Intellectual disability v3.1520 ISCA-37443-Loss Arina Puzriakova commented on Region: ISCA-37443-Loss
Intellectual disability v3.1520 ISCA-37439-Gain Arina Puzriakova commented on Region: ISCA-37439-Gain
Intellectual disability v3.1520 ISCA-37433-Loss Arina Puzriakova commented on Region: ISCA-37433-Loss
Intellectual disability v3.1520 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Intellectual disability v3.1520 ISCA-37432-Gain Arina Puzriakova commented on Region: ISCA-37432-Gain
Intellectual disability v3.1520 ISCA-37431-Gain Arina Puzriakova commented on Region: ISCA-37431-Gain
Intellectual disability v3.1520 ISCA-37431-Loss Arina Puzriakova commented on Region: ISCA-37431-Loss
Intellectual disability v3.1520 ISCA-37425-Loss Arina Puzriakova commented on Region: ISCA-37425-Loss
Intellectual disability v3.1520 ISCA-37425-Gain Arina Puzriakova commented on Region: ISCA-37425-Gain
Intellectual disability v3.1520 ISCA-37424-Loss Arina Puzriakova commented on Region: ISCA-37424-Loss
Intellectual disability v3.1520 ISCA-37421-Gain Arina Puzriakova commented on Region: ISCA-37421-Gain
Intellectual disability v3.1520 ISCA-37421-Loss Arina Puzriakova commented on Region: ISCA-37421-Loss
Intellectual disability v3.1520 ISCA-37420-Loss Arina Puzriakova commented on Region: ISCA-37420-Loss
Intellectual disability v3.1520 ISCA-37418-Gain Arina Puzriakova commented on Region: ISCA-37418-Gain
Intellectual disability v3.1520 ISCA-37418-Loss Arina Puzriakova commented on Region: ISCA-37418-Loss
Intellectual disability v3.1520 ISCA-37415-Loss Arina Puzriakova commented on Region: ISCA-37415-Loss
Intellectual disability v3.1520 ISCA-37415-Gain Arina Puzriakova commented on Region: ISCA-37415-Gain
Intellectual disability v3.1520 ISCA-37411-Loss Arina Puzriakova commented on Region: ISCA-37411-Loss
Intellectual disability v3.1520 ISCA-37405-Loss Arina Puzriakova commented on Region: ISCA-37405-Loss
Intellectual disability v3.1520 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss
Intellectual disability v3.1520 ISCA-37404-Gain Arina Puzriakova commented on Region: ISCA-37404-Gain
Intellectual disability v3.1520 ISCA-37400-Loss Arina Puzriakova commented on Region: ISCA-37400-Loss
Intellectual disability v3.1520 ISCA-37400-Gain Arina Puzriakova commented on Region: ISCA-37400-Gain
Intellectual disability v3.1520 ISCA-37397-Loss Arina Puzriakova commented on Region: ISCA-37397-Loss
Intellectual disability v3.1520 ISCA-37397-Gain Arina Puzriakova commented on Region: ISCA-37397-Gain
Intellectual disability v3.1520 ISCA-37408-Loss Ivone Leong commented on Region: ISCA-37408-Loss
Intellectual disability v3.1520 ISCA-37406-Loss Ivone Leong commented on Region: ISCA-37406-Loss
Intellectual disability v3.1520 ISCA-37401-Loss Ivone Leong commented on Region: ISCA-37401-Loss
Intellectual disability v3.1520 ISCA-37396-Loss Ivone Leong commented on Region: ISCA-37396-Loss
Intellectual disability v3.1520 ISCA-46295-Loss Ivone Leong commented on Region: ISCA-46295-Loss
Intellectual disability v3.1520 ISCA-46290-Gain Ivone Leong commented on Region: ISCA-46290-Gain
Intellectual disability v3.1520 ISCA-37500-Loss Ivone Leong commented on Region: ISCA-37500-Loss
Intellectual disability v3.1520 ISCA-37486-Loss Ivone Leong commented on Region: ISCA-37486-Loss
Intellectual disability v3.1520 ISCA-37478-Loss Ivone Leong commented on Region: ISCA-37478-Loss
Intellectual disability v3.1520 ISCA-37394-Loss Ivone Leong commented on Region: ISCA-37394-Loss
Intellectual disability v3.1520 ISCA-37393-Gain Ivone Leong commented on Region: ISCA-37393-Gain
Intellectual disability v3.1520 ISCA-37390-Loss Ivone Leong commented on Region: ISCA-37390-Loss
Intellectual disability v3.1520 ISCA-37392-Loss Arina Puzriakova commented on Region: ISCA-37392-Loss
Intellectual disability v3.1520 ISCA-37392-Gain Arina Puzriakova commented on Region: ISCA-37392-Gain
Intellectual disability v3.1520 ISCA-37494-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37494-Loss was changed from None to .
Required Overlap Percentage for ISCA-37494-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37494-Gain Arina Puzriakova Haploinsufficiency Score for ISCA-37494-Gain was changed from None to .
Required Overlap Percentage for ISCA-37494-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37439-Gain Arina Puzriakova GRCh38 position for ISCA-37439-Gain was changed from 154336276-154660745 to 154396223-154555683.
Required Overlap Percentage for ISCA-37439-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37468-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37468-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-46290-Gain Arina Puzriakova GRCh38 position for ISCA-46290-Gain was changed from 48447780-52444265 to 48447780-52444264.
Required Overlap Percentage for ISCA-46290-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-46299-Gain Arina Puzriakova Haploinsufficiency Score for ISCA-46299-Gain was changed from None to .
Required Overlap Percentage for ISCA-46299-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37423-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37423-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37423-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37423-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37392-Loss Arina Puzriakova GRCh38 position for ISCA-37392-Loss was changed from 73330451-74728175 to 73330452-74728172.
Required Overlap Percentage for ISCA-37392-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37392-Gain Arina Puzriakova GRCh38 position for ISCA-37392-Gain was changed from 73330451-74728175 to 73330452-74728172.
Required Overlap Percentage for ISCA-37392-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37425-Loss Arina Puzriakova GRCh38 position for ISCA-37425-Loss was changed from 176301975-177586960 to 176301976-177620792.
Required Overlap Percentage for ISCA-37425-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37425-Gain Arina Puzriakova GRCh38 position for ISCA-37425-Gain was changed from 176301975-177586960 to 176301976-177620792.
Required Overlap Percentage for ISCA-37425-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37390-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37390-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37429-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37429-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37443-Loss Arina Puzriakova GRCh38 position for ISCA-37443-Loss was changed from 196029183-197617794 to 196029183-197617791.
Required Overlap Percentage for ISCA-37443-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37394-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37394-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37405-Loss Arina Puzriakova GRCh38 position for ISCA-37405-Loss was changed from 110122329-110205017 to 110104531-110228181.
Haploinsufficiency Score for ISCA-37405-Loss was changed from 3 to 30.
Required Overlap Percentage for ISCA-37405-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37440-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37440-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37408-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37408-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37393-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37393-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37397-Loss Arina Puzriakova GRCh38 position for ISCA-37397-Loss was changed from 21443089-23306926 to 21562828-23306924.
Required Overlap Percentage for ISCA-37397-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37397-Gain Arina Puzriakova GRCh38 position for ISCA-37397-Gain was changed from 21443089-23306926 to 21562828-23306924.
Required Overlap Percentage for ISCA-37397-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37446-Loss Arina Puzriakova GRCh38 position for ISCA-37446-Loss was changed from 18924718-21111384 to 18924718-21111383.
Required Overlap Percentage for ISCA-37446-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37446-Gain Arina Puzriakova GRCh38 position for ISCA-37446-Gain was changed from 18924718-21111384 to 18924718-21111383.
Required Overlap Percentage for ISCA-37446-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37433-Loss Arina Puzriakova GRCh38 position for ISCA-37433-Loss was changed from 18924718-20299686 to 18924718-20299685.
Required Overlap Percentage for ISCA-37433-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37433-Gain Arina Puzriakova GRCh38 position for ISCA-37433-Gain was changed from 18924718-20299686 to 18924718-20299685.
Required Overlap Percentage for ISCA-37433-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37493-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37493-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37421-Loss Arina Puzriakova GRCh38 position for ISCA-37421-Loss was changed from 147105904-147922392 to 147105904-147917509.
Required Overlap Percentage for ISCA-37421-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37421-Gain Arina Puzriakova GRCh38 position for ISCA-37421-Gain was changed from 147105904-147922392 to 147105904-147917509.
Required Overlap Percentage for ISCA-37421-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37434-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37434-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37501-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37501-Loss was changed from None to .
Required Overlap Percentage for ISCA-37501-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37420-Loss Arina Puzriakova GRCh38 position for ISCA-37420-Loss was changed from 45608879-46087510 to 45627800-46087514.
Required Overlap Percentage for ISCA-37420-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37432-Gain Arina Puzriakova GRCh38 position for ISCA-37432-Gain was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37431-Loss Arina Puzriakova GRCh38 position for ISCA-37431-Loss was changed from 30835804-31891648 to 30780079-31937008.
Required Overlap Percentage for ISCA-37431-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37431-Gain Arina Puzriakova GRCh38 position for ISCA-37431-Gain was changed from 30835804-31891648 to 30780079-31937008.
Triplosensitivity Score for ISCA-37431-Gain was changed from 3 to 2.
Required Overlap Percentage for ISCA-37431-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37430-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37430-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37430-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37430-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37418-Loss Arina Puzriakova GRCh38 position for ISCA-37418-Loss was changed from 16853797-20316338 to 16906714-20309889.
Required Overlap Percentage for ISCA-37418-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37418-Gain Arina Puzriakova GRCh38 position for ISCA-37418-Gain was changed from 16853797-20316338 to 16906714-20309889.
Required Overlap Percentage for ISCA-37418-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37406-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37406-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37415-Loss Arina Puzriakova GRCh38 position for ISCA-37415-Loss was changed from 15410597-16198411 to 15417854-16198408.
Required Overlap Percentage for ISCA-37415-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37415-Gain Arina Puzriakova GRCh38 position for ISCA-37415-Gain was changed from 15410597-16198411 to 15417854-16198408.
Required Overlap Percentage for ISCA-37415-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37400-Loss Arina Puzriakova GRCh38 position for ISCA-37400-Loss was changed from 29638675-30188534 to 29638676-30188531.
Required Overlap Percentage for ISCA-37400-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37400-Gain Arina Puzriakova GRCh38 position for ISCA-37400-Gain was changed from 29638675-30188534 to 29638676-30188531.
Required Overlap Percentage for ISCA-37400-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37486-Loss Arina Puzriakova GRCh38 position for ISCA-37486-Loss was changed from 28811313-29035181 to 28811314-29035178.
Required Overlap Percentage for ISCA-37486-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37500-Loss Arina Puzriakova GRCh38 position for ISCA-37500-Loss was changed from 82534141-84045981 to 82534140-84045981.
Required Overlap Percentage for ISCA-37500-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37396-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37396-Loss was changed from None to .
Required Overlap Percentage for ISCA-37396-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-46295-Loss Arina Puzriakova GRCh38 position for ISCA-46295-Loss was changed from 31727418-32153205 to 31727418-32153204.
Required Overlap Percentage for ISCA-46295-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37411-Loss Arina Puzriakova GRCh38 position for ISCA-37411-Loss was changed from 30844901-32153207 to 30900686-32153204.
Required Overlap Percentage for ISCA-37411-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37478-Gain Arina Puzriakova GRCh38 position for ISCA-37478-Gain was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37404-Gain Arina Puzriakova GRCh38 position for ISCA-37404-Gain was changed from 22782170-28134729 to 22782170-28134728.
Required Overlap Percentage for ISCA-37404-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37401-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37401-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37441-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37441-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37424-Loss Arina Puzriakova GRCh38 position for ISCA-37424-Loss was changed from 79923892-86983483 to 79923087-86979631.
Required Overlap Percentage for ISCA-37424-Loss was changed from 80 to 60.
Intellectual disability v3.1519 FAR1 Sarah Leigh reviewed gene: FAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25439727, 30561787; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.1519 FAR1 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: FAR1.
Intellectual disability v3.1519 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG
Intellectual disability v3.1519 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Intellectual disability v3.1519 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Intellectual disability v3.1519 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Intellectual disability v3.1519 FMR1_CGG Sarah Leigh commented on STR: FMR1_CGG
Intellectual disability v3.1519 C9orf72_GGGGCC Eleanor Williams commented on STR: C9orf72_GGGGCC
Intellectual disability v3.1519 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Intellectual disability v3.1519 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Intellectual disability v3.1519 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Intellectual disability v3.1519 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Intellectual disability v3.1519 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Intellectual disability v3.1519 CACNA1I Ivone Leong Tag Q4_21_rating was removed from gene: CACNA1I.
Intellectual disability v3.1519 ZNF699 Ivone Leong Tag Q4_21_rating was removed from gene: ZNF699.
Intellectual disability v3.1519 YIPF5 Ivone Leong Tag Q2_21_rating was removed from gene: YIPF5.
Intellectual disability v3.1519 WDR4 Ivone Leong Tag Q2_21_rating was removed from gene: WDR4.
Intellectual disability v3.1519 VPS41 Ivone Leong Tag Q2_21_rating was removed from gene: VPS41.
Intellectual disability v3.1519 VPS11 Ivone Leong Tag Q2_21_rating was removed from gene: VPS11.
Intellectual disability v3.1519 UFSP2 Ivone Leong Tag Q2_21_rating was removed from gene: UFSP2.
Tag Q2_21_expert_review was removed from gene: UFSP2.
Intellectual disability v3.1519 UBE4A Ivone Leong Tag Q2_21_rating was removed from gene: UBE4A.
Intellectual disability v3.1519 TP73 Ivone Leong Tag Q3_21_rating was removed from gene: TP73.
Intellectual disability v3.1519 TNPO2 Ivone Leong Tag Q3_21_rating was removed from gene: TNPO2.
Intellectual disability v3.1519 TMEM222 Ivone Leong Tag Q2_21_rating was removed from gene: TMEM222.
Intellectual disability v3.1519 TCF7L2 Ivone Leong Tag Q4_21_rating was removed from gene: TCF7L2.
Intellectual disability v3.1519 SYNCRIP Ivone Leong Tag Q3_21_rating was removed from gene: SYNCRIP.
Intellectual disability v3.1519 SPTBN1 Ivone Leong Tag Q3_21_rating was removed from gene: SPTBN1.
Intellectual disability v3.1519 SPEN Ivone Leong Tag Q2_21_rating was removed from gene: SPEN.
Intellectual disability v3.1519 SNIP1 Ivone Leong Tag Q4_21_expert_review was removed from gene: SNIP1.
Intellectual disability v3.1519 SMARCA5 Ivone Leong Tag Q2_21_rating was removed from gene: SMARCA5.
Tag Q2_21_NHS_review was removed from gene: SMARCA5.
Intellectual disability v3.1519 SIN3B Ivone Leong Tag Q2_21_rating was removed from gene: SIN3B.
Intellectual disability v3.1519 SIAH1 Ivone Leong Tag Q2_21_rating was removed from gene: SIAH1.
Intellectual disability v3.1519 SCYL1 Ivone Leong Tag Q2_21_rating was removed from gene: SCYL1.
Intellectual disability v3.1519 SATB1 Ivone Leong Tag Q2_21_rating was removed from gene: SATB1.
Intellectual disability v3.1519 RFX7 Ivone Leong Tag Q3_21_rating was removed from gene: RFX7.
Intellectual disability v3.1519 RFX4 Ivone Leong Tag Q3_21_rating was removed from gene: RFX4.
Intellectual disability v3.1519 RFX3 Ivone Leong Tag Q3_21_rating was removed from gene: RFX3.
Intellectual disability v3.1519 PTPN4 Ivone Leong Tag Q3_21_rating was removed from gene: PTPN4.
Intellectual disability v3.1519 PRICKLE2 Ivone Leong Tag Q4_21_rating was removed from gene: PRICKLE2.
Intellectual disability v3.1519 PIGC Ivone Leong Tag Q2_21_rating was removed from gene: PIGC.
Intellectual disability v3.1519 PIDD1 Ivone Leong Tag Q3_21_rating was removed from gene: PIDD1.
Intellectual disability v3.1519 PI4KA Ivone Leong Tag Q3_21_rating was removed from gene: PI4KA.
Intellectual disability v3.1519 PGM2L1 Ivone Leong Tag Q3_21_rating was removed from gene: PGM2L1.
Intellectual disability v3.1519 PCDHGC4 Ivone Leong Tag Q3_21_rating was removed from gene: PCDHGC4.
Intellectual disability v3.1519 OTUD5 Ivone Leong Tag Q2_21_rating was removed from gene: OTUD5.
Intellectual disability v3.1519 NEUROD2 Ivone Leong Tag Q2_21_rating was removed from gene: NEUROD2.
Intellectual disability v3.1519 NCKAP1 Ivone Leong Tag Q2_21_rating was removed from gene: NCKAP1.
Intellectual disability v3.1519 NCDN Ivone Leong Tag Q2_21_rating was removed from gene: NCDN.
Intellectual disability v3.1519 MINPP1 Ivone Leong Tag Q2_21_rating was removed from gene: MINPP1.
Intellectual disability v3.1519 MED27 Ivone Leong Tag Q2_21_rating was removed from gene: MED27.
Intellectual disability v3.1519 MAP1B Ivone Leong Tag Q3_21_rating was removed from gene: MAP1B.
Intellectual disability v3.1519 LINGO4 Ivone Leong Tag Q3_21_rating was removed from gene: LINGO4.
Intellectual disability v3.1519 KCND2 Ivone Leong Tag Q4_21_rating was removed from gene: KCND2.
Intellectual disability v3.1519 KDM3B Ivone Leong Tag Q2_21_rating was removed from gene: KDM3B.
Intellectual disability v3.1519 KCNN2 Ivone Leong Tag Q2_21_rating was removed from gene: KCNN2.
Intellectual disability v3.1519 IMPDH2 Ivone Leong Tag Q3_21_rating was removed from gene: IMPDH2.
Intellectual disability v3.1519 HPDL Ivone Leong Tag Q2_21_rating was removed from gene: HPDL.
Intellectual disability v3.1519 HNMT Ivone Leong Tag Q3_21_rating was removed from gene: HNMT.
Tag Q3_21_NHS_review was removed from gene: HNMT.
Intellectual disability v3.1519 HIST1H4C Ivone Leong Tag Q3_21_rating was removed from gene: HIST1H4C.
Intellectual disability v3.1519 HID1 Ivone Leong Tag Q3_21_rating was removed from gene: HID1.
Intellectual disability v3.1519 GTF2E2 Ivone Leong Tag Q3_21_rating was removed from gene: GTF2E2.
Intellectual disability v3.1519 GNB2 Ivone Leong Tag Q3_21_rating was removed from gene: GNB2.
Intellectual disability v3.1519 GEMIN5 Ivone Leong Tag Q2_21_rating was removed from gene: GEMIN5.
Intellectual disability v3.1519 GABRD Ivone Leong Tag Q4_21_rating was removed from gene: GABRD.
Intellectual disability v3.1519 FARSA Ivone Leong Tag Q4_21_rating was removed from gene: FARSA.
Intellectual disability v3.1519 FBXO31 Ivone Leong Tag Q2_21_rating was removed from gene: FBXO31.
Intellectual disability v3.1519 ERBB4 Ivone Leong Tag Q2_21_rating was removed from gene: ERBB4.
Tag Q2_21_NHS_review was removed from gene: ERBB4.
Intellectual disability v3.1519 EMC10 Ivone Leong Tag Q2_21_rating was removed from gene: EMC10.
Intellectual disability v3.1519 EIF5A Ivone Leong Tag Q2_21_rating was removed from gene: EIF5A.
Intellectual disability v3.1519 DPYSL5 Ivone Leong Tag Q3_21_rating was removed from gene: DPYSL5.
Intellectual disability v3.1519 DPYS Ivone Leong Tag Q2_21_expert_review was removed from gene: DPYS.
Intellectual disability v3.1519 DPM2 Ivone Leong Tag Q2_21_rating was removed from gene: DPM2.
Intellectual disability v3.1519 DDB1 Ivone Leong Tag Q2_21_rating was removed from gene: DDB1.
Intellectual disability v3.1519 CAMK4 Ivone Leong Tag Q3_21_rating was removed from gene: CAMK4.
Intellectual disability v3.1519 CLCN3 Ivone Leong Tag Q3_21_rating was removed from gene: CLCN3.
Intellectual disability v3.1519 CHD5 Ivone Leong Tag Q3_21_rating was removed from gene: CHD5.
Intellectual disability v3.1519 CEP85L Ivone Leong Tag Q3_21_rating was removed from gene: CEP85L.
Intellectual disability v3.1519 CAPN15 Ivone Leong Tag Q2_21_rating was removed from gene: CAPN15.
Intellectual disability v3.1519 CPE Ivone Leong Tag Q3_21_rating was removed from gene: CPE.
Intellectual disability v3.1519 COPB2 Ivone Leong Tag Q3_21_rating was removed from gene: COPB2.
Intellectual disability v3.1519 CTC1 Ivone Leong Tag Q3_21_rating was removed from gene: CTC1.
Intellectual disability v3.1519 CDH15 Ivone Leong Tag watchlist was removed from gene: CDH15.
Intellectual disability v3.1519 CDH15 Ivone Leong Tag Q4_21_rating was removed from gene: CDH15.
Tag watchlist tag was added to gene: CDH15.
Intellectual disability v3.1519 BCAS3 Ivone Leong Tag Q2_21_rating was removed from gene: BCAS3.
Intellectual disability v3.1519 ATP9A Ivone Leong Tag Q4_21_rating was removed from gene: ATP9A.
Intellectual disability v3.1519 ATP1A3 Ivone Leong Tag Q3_21_expert_review was removed from gene: ATP1A3.
Intellectual disability v3.1519 ARFGEF1 Ivone Leong Tag Q4_21_rating was removed from gene: ARFGEF1.
Intellectual disability v3.1519 ARF1 Ivone Leong Tag Q3_21_rating was removed from gene: ARF1.
Intellectual disability v3.1519 AP1G1 Ivone Leong Tag Q3_21_rating was removed from gene: AP1G1.
Intellectual disability v3.1519 ANKRD17 Ivone Leong Tag Q2_21_rating was removed from gene: ANKRD17.
Intellectual disability v3.1519 ANK2 Ivone Leong Tag Q3_21_rating was removed from gene: ANK2.
Intellectual disability v3.1519 AGO1 Ivone Leong Tag Q2_21_expert_review was removed from gene: AGO1.
Intellectual disability v3.1519 ABHD16A Ivone Leong Tag Q4_21_rating was removed from gene: ABHD16A.
Intellectual disability v3.1519 POLR3B Ivone Leong Tag Q2_21_MOI was removed from gene: POLR3B.
Intellectual disability v3.1519 PHF6 Ivone Leong Tag Q4_21_MOI was removed from gene: PHF6.
Intellectual disability v3.1519 MED12 Ivone Leong Tag Q3_21_MOI was removed from gene: MED12.
Tag Q3_21_expert_review was removed from gene: MED12.
Intellectual disability v3.1519 HCCS Ivone Leong Tag Q4_21_MOI was removed from gene: HCCS.
Intellectual disability v3.1519 GRIK2 Ivone Leong Tag Q4_21_MOI was removed from gene: GRIK2.
Intellectual disability v3.1519 CLPB Ivone Leong Tag Q4_21_MOI was removed from gene: CLPB.
Intellectual disability v3.1519 ZNF699 Sarah Leigh commented on gene: ZNF699
Intellectual disability v3.1519 YIPF5 Sarah Leigh commented on gene: YIPF5
Intellectual disability v3.1519 WDR4 Sarah Leigh commented on gene: WDR4
Intellectual disability v3.1519 VPS41 Sarah Leigh commented on gene: VPS41
Intellectual disability v3.1519 VPS11 Sarah Leigh commented on gene: VPS11
Intellectual disability v3.1519 UFSP2 Sarah Leigh commented on gene: UFSP2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 UBE4A Sarah Leigh commented on gene: UBE4A
Intellectual disability v3.1519 TP73 Sarah Leigh commented on gene: TP73
Intellectual disability v3.1519 TNPO2 Sarah Leigh commented on gene: TNPO2
Intellectual disability v3.1519 TMEM222 Sarah Leigh commented on gene: TMEM222: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 TCF7L2 Sarah Leigh commented on gene: TCF7L2
Intellectual disability v3.1519 SYNCRIP Sarah Leigh commented on gene: SYNCRIP
Intellectual disability v3.1519 SPTBN1 Sarah Leigh commented on gene: SPTBN1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 SPEN Sarah Leigh commented on gene: SPEN
Intellectual disability v3.1519 SNIP1 Sarah Leigh commented on gene: SNIP1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 SMARCA5 Sarah Leigh commented on gene: SMARCA5
Intellectual disability v3.1519 SIN3B Sarah Leigh commented on gene: SIN3B
Intellectual disability v3.1519 SIAH1 Sarah Leigh commented on gene: SIAH1
Intellectual disability v3.1519 SCYL1 Sarah Leigh commented on gene: SCYL1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 SATB1 Sarah Leigh commented on gene: SATB1
Intellectual disability v3.1519 RFX7 Sarah Leigh commented on gene: RFX7
Intellectual disability v3.1519 RFX4 Sarah Leigh commented on gene: RFX4
Intellectual disability v3.1519 RFX3 Sarah Leigh commented on gene: RFX3
Intellectual disability v3.1519 PTPN4 Sarah Leigh commented on gene: PTPN4
Intellectual disability v3.1519 PRICKLE2 Sarah Leigh commented on gene: PRICKLE2
Intellectual disability v3.1519 POLR3B Sarah Leigh commented on gene: POLR3B
Intellectual disability v3.1519 PIGC Sarah Leigh commented on gene: PIGC
Intellectual disability v3.1519 PIDD1 Sarah Leigh commented on gene: PIDD1
Intellectual disability v3.1519 PI4KA Sarah Leigh commented on gene: PI4KA
Intellectual disability v3.1519 PHF6 Sarah Leigh commented on gene: PHF6
Intellectual disability v3.1519 PGM2L1 Sarah Leigh commented on gene: PGM2L1
Intellectual disability v3.1519 PCDHGC4 Sarah Leigh commented on gene: PCDHGC4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 OTUD5 Sarah Leigh commented on gene: OTUD5
Intellectual disability v3.1519 NEUROD2 Sarah Leigh commented on gene: NEUROD2
Intellectual disability v3.1519 NCKAP1 Sarah Leigh commented on gene: NCKAP1
Intellectual disability v3.1519 NCDN Sarah Leigh commented on gene: NCDN
Intellectual disability v3.1519 MINPP1 Sarah Leigh commented on gene: MINPP1
Intellectual disability v3.1519 MED27 Sarah Leigh commented on gene: MED27
Intellectual disability v3.1519 MED12 Sarah Leigh commented on gene: MED12
Intellectual disability v3.1519 MAP1B Sarah Leigh commented on gene: MAP1B
Intellectual disability v3.1519 LINGO4 Sarah Leigh commented on gene: LINGO4
Intellectual disability v3.1519 KDM3B Sarah Leigh commented on gene: KDM3B
Intellectual disability v3.1519 KCNN2 Sarah Leigh commented on gene: KCNN2
Intellectual disability v3.1519 KCND2 Sarah Leigh commented on gene: KCND2
Intellectual disability v3.1519 IMPDH2 Sarah Leigh commented on gene: IMPDH2
Intellectual disability v3.1519 HPDL Sarah Leigh commented on gene: HPDL
Intellectual disability v3.1519 HNMT Sarah Leigh commented on gene: HNMT
Intellectual disability v3.1519 HIST1H4C Sarah Leigh commented on gene: HIST1H4C
Intellectual disability v3.1519 HID1 Sarah Leigh commented on gene: HID1
Intellectual disability v3.1519 HCCS Sarah Leigh commented on gene: HCCS
Intellectual disability v3.1519 GTF2E2 Sarah Leigh commented on gene: GTF2E2
Intellectual disability v3.1519 GRIK2 Sarah Leigh commented on gene: GRIK2
Intellectual disability v3.1519 GNB2 Sarah Leigh commented on gene: GNB2
Intellectual disability v3.1519 GEMIN5 Sarah Leigh commented on gene: GEMIN5
Intellectual disability v3.1519 GABRD Sarah Leigh commented on gene: GABRD
Intellectual disability v3.1519 FBXO31 Sarah Leigh commented on gene: FBXO31
Intellectual disability v3.1519 FARSA Sarah Leigh commented on gene: FARSA
Intellectual disability v3.1519 ERBB4 Sarah Leigh commented on gene: ERBB4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 EMC10 Sarah Leigh commented on gene: EMC10
Intellectual disability v3.1519 EIF5A Sarah Leigh commented on gene: EIF5A
Intellectual disability v3.1519 DPYSL5 Sarah Leigh commented on gene: DPYSL5
Intellectual disability v3.1519 DPYS Sarah Leigh commented on gene: DPYS
Intellectual disability v3.1519 DPM2 Sarah Leigh commented on gene: DPM2
Intellectual disability v3.1519 DDB1 Sarah Leigh commented on gene: DDB1
Intellectual disability v3.1519 CTC1 Sarah Leigh commented on gene: CTC1
Intellectual disability v3.1519 CPE Sarah Leigh commented on gene: CPE
Intellectual disability v3.1519 COPB2 Sarah Leigh commented on gene: COPB2
Intellectual disability v3.1519 CLPB Sarah Leigh commented on gene: CLPB
Intellectual disability v3.1519 CLCN3 Sarah Leigh commented on gene: CLCN3
Intellectual disability v3.1519 CHD5 Sarah Leigh commented on gene: CHD5
Intellectual disability v3.1519 CEP85L Sarah Leigh commented on gene: CEP85L: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 CDH15 Sarah Leigh commented on gene: CDH15
Intellectual disability v3.1519 CAPN15 Sarah Leigh commented on gene: CAPN15
Intellectual disability v3.1519 CAMK4 Sarah Leigh commented on gene: CAMK4
Intellectual disability v3.1519 CACNA1I Sarah Leigh commented on gene: CACNA1I
Intellectual disability v3.1519 BCAS3 Sarah Leigh commented on gene: BCAS3
Intellectual disability v3.1519 ATP9A Sarah Leigh commented on gene: ATP9A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 ATP1A3 Sarah Leigh commented on gene: ATP1A3
Intellectual disability v3.1519 ARFGEF1 Sarah Leigh commented on gene: ARFGEF1
Intellectual disability v3.1519 ARF1 Sarah Leigh commented on gene: ARF1
Intellectual disability v3.1519 AP1G1 Sarah Leigh commented on gene: AP1G1
Intellectual disability v3.1519 ANKRD17 Sarah Leigh commented on gene: ANKRD17
Intellectual disability v3.1519 ANK2 Sarah Leigh commented on gene: ANK2
Intellectual disability v3.1519 AGO1 Sarah Leigh commented on gene: AGO1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 AFG3L2 Sarah Leigh commented on gene: AFG3L2: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 ABHD16A Sarah Leigh commented on gene: ABHD16A
Intellectual disability v3.1519 ZNF699 Ivone Leong Source Expert Review Green was added to ZNF699.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 YIPF5 Ivone Leong Source Expert Review Green was added to YIPF5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 WDR4 Ivone Leong Source Expert Review Green was added to WDR4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 VPS41 Ivone Leong Source Expert Review Green was added to VPS41.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 VPS11 Ivone Leong Source Expert Review Green was added to VPS11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 UFSP2 Ivone Leong Source Expert Review Green was added to UFSP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 UBE4A Ivone Leong Source Expert Review Green was added to UBE4A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 TP73 Ivone Leong Source Expert Review Green was added to TP73.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 TNPO2 Ivone Leong Source Expert Review Green was added to TNPO2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 TMEM222 Ivone Leong Source Expert Review Green was added to TMEM222.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 TCF7L2 Ivone Leong Source Expert Review Green was added to TCF7L2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SYNCRIP Ivone Leong Source Expert Review Green was added to SYNCRIP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SPTBN1 Ivone Leong Source Expert Review Green was added to SPTBN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SPEN Ivone Leong Source Expert Review Green was added to SPEN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SNIP1 Ivone Leong Source Expert Review Green was added to SNIP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SMARCA5 Ivone Leong Source Expert Review Green was added to SMARCA5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SIN3B Ivone Leong Source Expert Review Green was added to SIN3B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SIAH1 Ivone Leong Source Expert Review Green was added to SIAH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SCYL1 Ivone Leong Source Expert Review Green was added to SCYL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SATB1 Ivone Leong Source Expert Review Green was added to SATB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 RFX7 Ivone Leong Source Expert Review Green was added to RFX7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 RFX4 Ivone Leong Source Expert Review Green was added to RFX4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 RFX3 Ivone Leong Source Expert Review Green was added to RFX3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PTPN4 Ivone Leong Source Expert Review Green was added to PTPN4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PRICKLE2 Ivone Leong Source Expert Review Green was added to PRICKLE2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 POLR3B Ivone Leong Source NHS GMS was added to POLR3B.
Mode of inheritance for gene POLR3B was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1519 PIGC Ivone Leong Source Expert Review Green was added to PIGC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PIDD1 Ivone Leong Source Expert Review Green was added to PIDD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PI4KA Ivone Leong Source Expert Review Green was added to PI4KA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PHF6 Ivone Leong Source NHS GMS was added to PHF6.
Mode of inheritance for gene PHF6 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 v3.1519 PGM2L1 Ivone Leong Source Expert Review Green was added to PGM2L1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PCDHGC4 Ivone Leong Source Expert Review Green was added to PCDHGC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 OTUD5 Ivone Leong Source Expert Review Green was added to OTUD5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 NEUROD2 Ivone Leong Source Expert Review Green was added to NEUROD2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 NCKAP1 Ivone Leong Source Expert Review Green was added to NCKAP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 NCDN Ivone Leong Source Expert Review Green was added to NCDN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 MINPP1 Ivone Leong Source Expert Review Green was added to MINPP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 MED27 Ivone Leong Source Expert Review Green was added to MED27.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 MED12 Ivone Leong Source NHS GMS was added to MED12.
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, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1519 MAP1B Ivone Leong Source Expert Review Green was added to MAP1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 LINGO4 Ivone Leong Source Expert Review Green was added to LINGO4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 KDM3B Ivone Leong Source Expert Review Green was added to KDM3B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 KCNN2 Ivone Leong Source Expert Review Green was added to KCNN2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 KCND2 Ivone Leong Source Expert Review Green was added to KCND2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 IMPDH2 Ivone Leong Source Expert Review Green was added to IMPDH2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 HPDL Ivone Leong Source Expert Review Green was added to HPDL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 HNMT Ivone Leong Source Expert Review Green was added to HNMT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 HIST1H4C Ivone Leong Source Expert Review Green was added to HIST1H4C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 HID1 Ivone Leong Source Expert Review Green was added to HID1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 HCCS Ivone Leong Source NHS GMS was added to HCCS.
Mode of inheritance for gene HCCS 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 v3.1519 GTF2E2 Ivone Leong Source Expert Review Green was added to GTF2E2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 GRIK2 Ivone Leong Source NHS GMS was added to GRIK2.
Mode of inheritance for gene GRIK2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1519 GNB2 Ivone Leong Source Expert Review Green was added to GNB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 GEMIN5 Ivone Leong Source Expert Review Green was added to GEMIN5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 GABRD Ivone Leong Source Expert Review Green was added to GABRD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 FBXO31 Ivone Leong Source Expert Review Green was added to FBXO31.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 FARSA Ivone Leong Source Expert Review Green was added to FARSA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ERBB4 Ivone Leong Source Expert Review Green was added to ERBB4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 EMC10 Ivone Leong Source Expert Review Green was added to EMC10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 EIF5A Ivone Leong Source Expert Review Green was added to EIF5A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 DPYSL5 Ivone Leong Source Expert Review Green was added to DPYSL5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 DPYS Ivone Leong Source Expert Review Green was added to DPYS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 DPM2 Ivone Leong Source Expert Review Green was added to DPM2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 DDB1 Ivone Leong Source Expert Review Green was added to DDB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CTC1 Ivone Leong Source Expert Review Amber was added to CTC1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1519 CPE Ivone Leong Source Expert Review Green was added to CPE.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 COPB2 Ivone Leong Source Expert Review Green was added to COPB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CLPB Ivone Leong Source NHS GMS was added to CLPB.
Mode of inheritance for gene CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1519 CLCN3 Ivone Leong Source Expert Review Green was added to CLCN3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CHD5 Ivone Leong Source Expert Review Green was added to CHD5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CEP85L Ivone Leong Source Expert Review Green was added to CEP85L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CDH15 Ivone Leong Source Expert Review Red was added to CDH15.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1519 CAPN15 Ivone Leong Source Expert Review Green was added to CAPN15.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CAMK4 Ivone Leong Source Expert Review Green was added to CAMK4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CACNA1I Ivone Leong Source Expert Review Green was added to CACNA1I.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 BCAS3 Ivone Leong Source Expert Review Green was added to BCAS3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ATP9A Ivone Leong Source Expert Review Green was added to ATP9A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ATP1A3 Ivone Leong Source Expert Review Green was added to ATP1A3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ARFGEF1 Ivone Leong Source Expert Review Green was added to ARFGEF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ARF1 Ivone Leong Source Expert Review Green was added to ARF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 AP1G1 Ivone Leong Source Expert Review Green was added to AP1G1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ANKRD17 Ivone Leong Source Expert Review Green was added to ANKRD17.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ANK2 Ivone Leong Source Expert Review Green was added to ANK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 AGO1 Ivone Leong Source Expert Review Green was added to AGO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 AFG3L2 Ivone Leong Source NHS GMS was added to AFG3L2.
Intellectual disability v3.1519 ABHD16A Ivone Leong Source Expert Review Green was added to ABHD16A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1518 CPSF3 Konstantinos Varvagiannis gene: CPSF3 was added
gene: CPSF3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CPSF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPSF3 were set to 35121750
Phenotypes for gene: CPSF3 were set to Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures
Penetrance for gene: CPSF3 were set to Complete
Review for gene: CPSF3 was set to AMBER
Added comment: Arnadottir (2022 - PMID: 35121750) describe the phenotype associated with biallelic CPSF3 pathogenic variants.

Based on WGS of 56,969 Icelanders and imputing the genotype of another 153,054 chip-genotyped Icelanders, the authors identified missense variants with a deficit of homozygous carriers to what would be expected based on AF. (For variants with MAF>0.4%, for which >=3 hmz carriers would be expected by H-W equilibrium, no identified hmz carriers within this cohort/dataset). A total of 114 such missense variants was identified.

5 of these SNVs, among which a CPSF3 one (NM_016207.3:c.1403G>A / p.Gly468Glu), were however observed in a series of 764 individuals investigated with clinical WGS at the National University Hospital.

The CPSF3 variant with a MAF of 0.41% (3 hmz expected but none observed in the population set) was found in homozygosity in 2 closely related individuals, both investigated for FTT, severe DD, ID, microcephaly, seizures but remaining unresolved following WGS with no other candidate variants.

Using genealogical information from the db of deCODE genetics, the authors identified 3 couples from the 153k genotyped Icelanders where both partners were htz carriers for this SNV. These 3 couples had 10 offspring, 4 of whom deceased but with the same phenotypic features as above (hypotonia 4/4, ID 4/4, seizures 3/4, microcephaly 2/4). Paraffin embedded samples of 2 of these children and WG & Sanger sequencing confirmed hmz for Gly468Glu in 2 sibs, without other candidate variants. Samples of the 2 other individuals were N/A.

Through GeneMatcher 2 additional first-cousin patients from Mexico were identified, being hmz for another CPSF3 variant (c.1061T>C/p.Ile354Thr) and having overlapping phenotype of abnormal muscle tone, ID, seizures and microcephaly. There were no other variants in WES analysis.

mRNA studies in WBCs from Gly468Glu htz carriers did not reveal reduced levels and W.Blot of lymphocytes from a hmz individual confirmed expression, overall suggesting that the variant does not affect the protein levels but presumably the function.

CPSF3 encodes cleavage and polyadenylation specificity factor 3, a 684 aa protein, subunit of the cleavage and polyadenylation specificity factor compex. As discussed, cleavage and polyadenylation of the 3' of pre-mRNAs is necessary before transport out of the nucleus with CPSF playing a crucial role in the process of cleavage.

CPSF3 ko mice exhibit embryonic lethality, while in yeast mutations in key residues of the CPSF3 homolog are lethal.

In gnomAD, CPSF3 has a pLI of 0, z-score of 3.61 with no homozygotes for pLoF variants in 141k individuals (or ~57k WGS Icelanders).

The 2 missense variants concerned highly conserved residues (GERP ~5.8). Both are hypothesized to affect the ability of the protein to bind other factors involved in pre-mRNA cleavage.

Overall the authors speculate that not only complete loss of CPSF3 would result in drastic phenotypic effects - as in the murine model - but also variants altering its enzymatic function.

There is currently no CPSF3-related phenotype in OMIM, G2P, SysID, The gene is included with green rating in the ID, epilepsy and microcephaly panels in PanelApp Australia.

Consider inclusion probably with amber rating (Highly consistent phenotype, biological function, evidence from animal models. 2 identified variants, authors state that follow-up functional studies are needed). Also consider inclusion in other possibly relevant panels.
Sources: Literature
Intellectual disability v3.1518 NRCAM Konstantinos Varvagiannis gene: NRCAM was added
gene: NRCAM was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRCAM were set to 35108495
Phenotypes for gene: NRCAM were set to Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face
Penetrance for gene: NRCAM were set to Complete
Review for gene: NRCAM was set to GREEN
Added comment: Kurolap et al (2022 - PMID: 35108495) describe the phenotype of 10 individuals (from 8 families) with biallelic variants in NRCAM.

Features included tone abnormalities (hypotonia in 4/10, hypertonia/spasticity in 4/10), DD (8/10 - 7 families) and cognitive impairment (in 7/10 - 6 fam), neuropathy (4/10 - incl. 2 sibs without DD/ID). Other phenotypes incl. FTT (2/8), microcephaly (3/6), variable behavioral issues (3/5), abnormalities from the eyes/vision (6/8 - cataract in 2), abnormal hearing (3/7) or skeletal findings (8/9 - incl. scoliosis in 5). Nonspecific facial features were reported in 5/8.

Previous metabolic, genetic (incl. karyotype or CMA, FMR1, testing for Steinert disease or SMA) or other work-up (e.g. muscle biopsy) is reported for several subjects but was normal/non-diagnostic.

All were investigated by WES/WGS which revealed biallelic NRCAM variants. Sanger sequencing was used for confirmation and segregation analyses, with compatible results in several affected/unaffected sibs tested. There were no alternative explanations for the NDD phenotype with the exception of one subject with a mosaic functionally characterized LP KRAS variant suspected to contribute to his phenotype.

NRCAM encodes neuronal cell adhesion molecule (CAM). CAMs are membrane bound proteins with important role in tissue morphogenesis and maintenance. They mediate interactions between neighboring cells or cells and the extracellular matrix. The L1 subgroup of immunoglobulin CAMS - consisting of L1CAM, neurofascin, NRCAM, CHL1 - is the most abundant in the CNS with several critical functions in CNS development, among others in neural cell differentiation, axonal growth and guidance, myelination, synapse formation. Pathogenic L1CAM (XL) and NFASC variants (AR) are associated with NDD.

Different missense (N=7), stopgain/frameshift (N=3), a splice variant (NM_001037132.2:c.2647-2A>G) as well as a deep intronic one (c.230+824G>C / rs575851831). Variants occurred in different domains with a cluster (42%) in the fibronectin III domain.

Missense SNVs were ultrarare or not present in gnomAD, occurred in conserved residues, with several in silico predictions in favor of a deleterious effect. Structural modelling suggested that all substitutions occurred at residues exposed to solvent and possible abrogated interaction with other proteins.

There were no expression studies performed at the mRNA/protein level. The splice variant is predicted to cause ex22 skipping leading to frameshift. The deep intronic variant is predicted to disrupt a site for spl. regulator SC35 and may cause activation of a cryptic acceptor site with inclusion of a cryptic exon.

The zebrafish nrcama gene is the sole ortholog of human NRCAM, with another gene proposed as possible ortholog (nrcamb) mapping upon BLAST analysis to cntn1a. The authors performed CRISPR-Cas9 mutagenesis in zebrafish introducing a partial deletion of ex18 and 19. Mutant zebrafish were viable, displayed altered axonal projections and abnormal swimming behavior (increased movement in darkness).

Currently, there is no NRCAM-associated phenotype in OMIM/G2P/SysID. PanelApp Australia includes NRCAM in its ID panel with green rating.

Consider inclusion probably with green (>3 individuals/families/variants, segregation, gene in the L1-Ig CAM family causing NDD, zebrafish model) or amber rating (ID not a universal feature, variant effect not studied).
Sources: Literature
Intellectual disability v3.1518 TIAM1 Konstantinos Varvagiannis gene: TIAM1 was added
gene: TIAM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TIAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIAM1 were set to 35240055; 33328293
Phenotypes for gene: TIAM1 were set to Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology
Penetrance for gene: TIAM1 were set to Complete
Review for gene: TIAM1 was set to AMBER
Added comment: Lu et al (2022 - PMID: 35240055) describe 5 individuals (from 4 families) with biallelic TIAM1 missense variants.

The phenotype overall corresponded to a neurodevelopmental disorder with DD (5/5), ID (4/4 individuals of relevant age - 3 families), speech delay (5/5), seizures (5/5 - onset: 2m-13y) and behavioral abnormalities (2/2, sibs with autism and ADHD). Several subjects had endocrine symptoms, namely hypothyroidism (N=3 - 2 families), Addison's disease (1) or hypomagnesemia (1). Non-consistent abnormalities were reported in (3/3) subjects who had a brain MRI.

Previous investigations were mentioned for 3 individuals (incl. 2 sibs) and included normal CMA and/or metabolic workup.

Singleton or trio exome sequencing (in one family) revealed biallelic missense TIAM1 variants.

6 different missense variants were reported, all ultra-rare or not present in gnomAD (also o/e:0.2, pLI:0.96), with CADD scores in favor of deleterious effect (NM_001353694.2): c.67C>T/p.Arg23Cys*, c.2584C>T/p.Leu862Phe*, c.983G>T/p.Gly328Val*, c.4640C>A/p.Ala1547Glu, c.1144G>C/p.Gly382Arg, c.4016C>T/p.Ala1339Val.

TIAM1 encodes a RAC1-specific guanine exchange factor (GEF), regulating RAC1 signaling pathways that in turn affect cell shape, migration, adhesion, growth, survival, and polarity, and influence actin cytoskeletal organization, endocytosis, and membrane trafficking. RAC1 signaling plays important role in control of neuronal morphogenesis and neurite outgrowth (based on the summary by Entrez and authors).

TIAM1 is highly expressed in human brain (GTEx).

The authors provide evidence that sif, the Drosophila ortholog, is expressed primarily in neurons of the fly CNS (but not in glia). Using different sif LoF mutant flies they demonstrate that loss of sif impairs viability. Surviving flies exhibited climbing defects and seizure-like behaviors, both significantly rescued upon UAS-sif expression. Neuronal specific sif knockdown resulted in similar phenotypes to ubiquitous knockdown, while glial knockdown did not result in climbing defects.

The semi-lethal phenotype could be fully rescued by expression of the fly sif cDNA, but only partially by human TIAM1 cDNA reference. Upon expression, 3 patient-variants (R23C, L862F, G328V) had variable rescue abilities similar to or lower (R23C) than TIAM1 Ref. TIAM1 Ref and variants could not rescue the neurological phenotypes though. Higher/ectopic expression of sif or TIAM1 Ref was toxic, which was also observed to a lesser extent for variants.

Overall, the evidence provided suggests that the 3 variants tested induce partial LoF.

In a recent study cited (PMID: 33328293), Tiam1 KO mice had simplified dendritic arbors, reduced spine density and diminished excitatory transmission in dentate gyrus. The authors comment that this mouse model presented only subtle behavioral abnormalities which they speculate may be secondary to GEF redundancy (eg. Tiam2).

There is no TIAM1-associated phenotype in OMIM/G2P/SysID. TIAM1 is included in PanelApp Australia in the ID and epilepsy panels with green rating.

Consider inclusion in the current panel with amber rating [As authors discuss: some phenotypic features differed in their small cohort and the contribution of other recessive conditions in 2 consanguineous families cannot be excluded. Also: in fig S1 only status of parents but not of affected/unaffected sibs is specified with the exception of Fam1].
Sources: Literature
Intellectual disability v3.1518 THUMPD1 Konstantinos Varvagiannis reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30237576, 35196516; Phenotypes: Global developmental delay, Intellectual disability, Microcephaly, Hearing abnormality, Abnormality of the eye, Febrile seizures, Behavioral abnormality, Abnormality of brain morphology, Abnormality of the face; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.1518 HEATR3 Konstantinos Varvagiannis gene: HEATR3 was added
gene: HEATR3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to 35213692
Phenotypes for gene: HEATR3 were set to Anemia; Thrombocytopenia; Growth delay; Short stature; Abnormality of the skeletal system; Abnormality of finger; Abnormality of the thumb; Intellectual disability; Obesity; Abnormality of the face
Penetrance for gene: HEATR3 were set to Complete
Review for gene: HEATR3 was set to AMBER
Added comment: O'Donohue et al (2022 - PMID: 35213692) describe the clinical features of 6 individuals (from 4 unrelated families) with biallelic pathogenic HEATR3 variants.

These included bone marrow failure (anemia/anemia and thrombocytopenia at presentation), short stature/growth retardation (4/6), facial features (5/6 - in some: straight eyebrows, d-s palpebral fissures, synophrys) and skeletal findings incl. disproportionately short fingers/thumb anomaly. ID was reported in 4/6 individuals from 3 families (all: mild ID | 2/6 without ID). The phenotype corresponded overall to a variant form Diamond-Blackfan anemia (DBA, disorder caused by variants in genes encoding for ribosomal proteins) with additional features.

The 1st family (2 affected sibs and parents) underwent WES, not diagnostic for DBA. Analysis suggested variants in HEATR3 (prioritized due to its potential role in ribosome biogenesis) and 4 additional genes as candidates. Collaboration in the European DBA consortium and national DBA consortia led to identification of additional families.

HEATR3 encodes Heat-repeat-containing protein 3 or symportin, a protein that co-imports uL5 (encoded by RPL11) and uL18 (RPL5) in the nucleus where they assemble with 5S rRNA to form 5S RNP. The 5S RNP complex incorporates with maturing large ribosomal subunits to form the central protuberance. When 5S RNP is not incorporated, it accumulates and associates with Hdm2 ubiquitin ligase, the later normally targeting p53 proteasomal degradation.

The following missense and splice variants were identified (NM_182922):
- c.1751G>Α/p.(Gly584Glu) hmz
- c.1337G>A/p.(Cys446Tyr) hmz
- c.399+1G>T in trans with c.719C>T/p.(Pro240Leu)
- c.400T>C/p.(Cys134Arg) hmz

Variants were confirmed with Sanger sequencing. They were dispersed across HEATR3 without clustering although they affect residues either in the ARM (38-320) or HEAT (415-675) repeat domains, at positions evolutionary conserved, with in silico predictions in favor of a deleterious effect. With the exception of Cys134Arg (AF:4.11x10-6/no hmz), all were absent from gnomAD.

Studies in yeast suggested that deletions in symportin gene (syo1) lead to a mild growth defect and accumulation of 40S subunits. Similarly, two yeast strains engineered to test for the effect of the p.Gly584Glu (yeast p.Gly522Glu/Ala) exhibited growth defect and ribosomal subunit imbalance, both restored by wt Syo1.

HA-tagged HEATR3 in HeLa cells suggested that the co-translational capture mechanism to chaperone uL18 (RPL5) is conserved in human cells but was not observed upon expression of the p.Cys446Tyr variant.

While HEATR3 transcription was not affected in LCLs from individuals hmz for Gly584Glu or Cys446Tyr, protein levels were barely detectable, suggesting destabilization of the protein.

While uL18 accumulates in cytoplasm and nucleus with expected enrichment in nucleolus, upon siRNA knockdown of HEATR3 in HeLa cells this enrichment was lost. Studies in fibroblasts (Gly584Glu) demonstrated reduced uL18 nuclear staining. Overall, HEATR3 was suggested to be important for nuclear import of uL18 (though not for uL5).

LCL studies demonstrated pre-rRNA processing defects in patient cells with accumulation of 32S and 12S pre-rRNAs, the former being reminiscent of accumulations observed in individuals with RPL5- and RPL11-related DBA. Expression of wt HEATR3 restored processing defects.

LCLs from affected individuals revealed loss of free 60S subunits (as in yeast) with expression of wt cDNA restoring Nl levels.

Western blots of LCLs demonstrated that the levels of uL5, uL18 and p53 were not affected (the latter also observed in RPL5-related DBA)

Studies of bone marrow smears from 2 affected individuals allowed to conclude in a strong defect in erythroid cell proliferation.

Currently, there is no HEATR3-associated phenotype in OMIM, PanelApp Australia, G2P or the SysID database.

Consider inclusion in the ID panel with amber (mild ID in >3 individuals/families/variants although not universal feature) or green rating. Also consider inclusion in other possibly relevant panels eg. for cytopenias/congenital anemias, short stature, etc.
Sources: Literature
Intellectual disability v3.1518 FMR1_CGG Arina Puzriakova Classified STR: FMR1_CGG as Green List (high evidence)
Intellectual disability v3.1518 FMR1_CGG Arina Puzriakova Str: fmr1_cgg has been classified as Green List (High Evidence).
Intellectual disability v3.1518 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Green List (high evidence)
Intellectual disability v3.1518 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Green List (High Evidence).
Intellectual disability v3.1515 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Source NHS GMS was added to STR: PPP2R2B_CAG.
Intellectual disability v3.1515 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Intellectual disability v3.1515 FMR1_CGG Arina Puzriakova Source NHS GMS was added to STR: FMR1_CGG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1515 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1515 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Source NHS GMS was added to STR: CSTB_CCCCGCCCCGCG.
Intellectual disability v3.1515 C9orf72_GGGGCC Arina Puzriakova Normal Number of Repeats for C9orf72_GGGGCC was changed from 30 to 24.
Pathogenic Number of Repeats for C9orf72_GGGGCC was changed from 30 to 200.
Source NHS GMS was added to STR: C9orf72_GGGGCC.
Intellectual disability v3.1515 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Source NHS GMS was added to STR: ATXN7_CAG.
Intellectual disability v3.1515 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN3_CAG.
Intellectual disability v3.1515 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Intellectual disability v3.1515 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Intellectual disability v3.1515 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN1_CAG.
Intellectual disability v3.1514 EXT2 Arina Puzriakova Tag for-review was removed from gene: EXT2.
Intellectual disability v3.1514 CTNND1 Arina Puzriakova Tag for-review was removed from gene: CTNND1.
Intellectual disability v3.1514 SLC12A6 Arina Puzriakova commented on gene: SLC12A6
Intellectual disability v3.1514 SLC12A6 Arina Puzriakova Tag for-review was removed from gene: SLC12A6.
Intellectual disability v3.1514 SCN8A Arina Puzriakova Tag for-review was removed from gene: SCN8A.
Intellectual disability v3.1514 CDK19 Arina Puzriakova Tag for-review was removed from gene: CDK19.
Intellectual disability v3.1514 ABCA2 Arina Puzriakova Tag for-review was removed from gene: ABCA2.
Intellectual disability v3.1514 PIGH Arina Puzriakova Tag for-review was removed from gene: PIGH.
Intellectual disability v3.1514 METTL5 Arina Puzriakova Tag for-review was removed from gene: METTL5.
Intellectual disability v3.1514 LMBRD2 Arina Puzriakova Tag for-review was removed from gene: LMBRD2.
Intellectual disability v3.1514 LIAS Arina Puzriakova Tag for-review was removed from gene: LIAS.
Intellectual disability v3.1514 CSNK1G1 Arina Puzriakova Tag for-review was removed from gene: CSNK1G1.
Intellectual disability v3.1514 ALG14 Arina Puzriakova Tag for-review was removed from gene: ALG14.
Intellectual disability v3.1514 AGO2 Arina Puzriakova Tag for-review was removed from gene: AGO2.
Intellectual disability v3.1514 PNPT1 Arina Puzriakova Tag for-review was removed from gene: PNPT1.
Intellectual disability v3.1514 SCO1 Arina Puzriakova Tag for-review was removed from gene: SCO1.
Intellectual disability v3.1514 FA2H Arina Puzriakova Tag for-review was removed from gene: FA2H.
Intellectual disability v3.1514 COX6B1 Arina Puzriakova Tag for-review was removed from gene: COX6B1.
Intellectual disability v3.1514 MPI Arina Puzriakova Tag for-review was removed from gene: MPI.
Intellectual disability v3.1514 VAMP1 Arina Puzriakova Tag watchlist was removed from gene: VAMP1.
Tag for-review was removed from gene: VAMP1.
Intellectual disability v3.1514 TRIM32 Arina Puzriakova Tag for-review was removed from gene: TRIM32.
Intellectual disability v3.1514 MGP Arina Puzriakova Tag for-review was removed from gene: MGP.
Intellectual disability v3.1514 LGI4 Arina Puzriakova Tag for-review was removed from gene: LGI4.
Intellectual disability v3.1514 HYLS1 Arina Puzriakova Tag for-review was removed from gene: HYLS1.
Intellectual disability v3.1514 HADH Arina Puzriakova Tag for-review was removed from gene: HADH.
Intellectual disability v3.1514 FLVCR1 Arina Puzriakova Tag for-review was removed from gene: FLVCR1.
Intellectual disability v3.1514 ATL1 Arina Puzriakova Tag for-review was removed from gene: ATL1.
Intellectual disability v3.1514 ANKH Arina Puzriakova Tag for-review was removed from gene: ANKH.
Intellectual disability v3.1514 AFG3L2 Arina Puzriakova Mode of inheritance for gene: AFG3L2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1513 AFG3L2 Arina Puzriakova Tag for-review was removed from gene: AFG3L2.
Tag Q2_21_MOI was removed from gene: AFG3L2.
Intellectual disability v3.1513 KCNC3 Arina Puzriakova Tag for-review was removed from gene: KCNC3.
Intellectual disability v3.1513 ALKBH8 Arina Puzriakova Tag for-review was removed from gene: ALKBH8.
Intellectual disability v3.1513 SOX3 Arina Puzriakova Tag for-review was removed from gene: SOX3.
Intellectual disability v3.1513 PRKD1 Arina Puzriakova Tag for-review was removed from gene: PRKD1.
Intellectual disability v3.1513 GPSM2 Arina Puzriakova Tag for-review was removed from gene: GPSM2.
Intellectual disability v3.1513 DDOST Arina Puzriakova Tag for-review was removed from gene: DDOST.
Intellectual disability v3.1513 CYP2U1 Arina Puzriakova Tag for-review was removed from gene: CYP2U1.
Intellectual disability v3.1513 AGPS Arina Puzriakova Tag for-review was removed from gene: AGPS.
Intellectual disability v3.1513 TMEM106B Arina Puzriakova Tag for-review was removed from gene: TMEM106B.
Intellectual disability v3.1513 NEMF Arina Puzriakova Tag for-review was removed from gene: NEMF.
Intellectual disability v3.1513 MPP5 Arina Puzriakova Tag for-review was removed from gene: MPP5.
Intellectual disability v3.1513 MAPK1 Arina Puzriakova Tag for-review was removed from gene: MAPK1.
Intellectual disability v3.1513 LMNB1 Arina Puzriakova Tag for-review was removed from gene: LMNB1.
Intellectual disability v3.1513 KIF21B Arina Puzriakova Tag for-review was removed from gene: KIF21B.
Intellectual disability v3.1513 JARID2 Arina Puzriakova Tag for-review was removed from gene: JARID2.
Intellectual disability v3.1513 FAM50A Arina Puzriakova Tag for-review was removed from gene: FAM50A.
Intellectual disability v3.1513 CEP120 Arina Puzriakova Tag for-review was removed from gene: CEP120.
Intellectual disability v3.1513 ZNF526 Arina Puzriakova Tag for-review was removed from gene: ZNF526.
Intellectual disability v3.1513 TFE3 Arina Puzriakova Tag for-review was removed from gene: TFE3.
Intellectual disability v3.1513 PIGQ Arina Puzriakova Tag for-review was removed from gene: PIGQ.
Intellectual disability v3.1513 KAT5 Arina Puzriakova Tag for-review was removed from gene: KAT5.
Intellectual disability v3.1513 ZNF335 Arina Puzriakova Tag for-review was removed from gene: ZNF335.
Intellectual disability v3.1513 ZIC1 Arina Puzriakova Tag for-review was removed from gene: ZIC1.
Intellectual disability v3.1513 SETD1A Arina Puzriakova Tag for-review was removed from gene: SETD1A.
Intellectual disability v3.1513 PET100 Arina Puzriakova Tag for-review was removed from gene: PET100.
Intellectual disability v3.1513 NUDT2 Arina Puzriakova Tag for-review was removed from gene: NUDT2.
Intellectual disability v3.1513 MFSD2A Arina Puzriakova Tag for-review was removed from gene: MFSD2A.
Intellectual disability v3.1513 MAPRE2 Arina Puzriakova Tag for-review was removed from gene: MAPRE2.
Intellectual disability v3.1513 CDH2 Arina Puzriakova Tag for-review was removed from gene: CDH2.
Intellectual disability v3.1513 SMG8 Arina Puzriakova Tag for-review was removed from gene: SMG8.
Intellectual disability v3.1513 LSS Arina Puzriakova Tag watchlist was removed from gene: LSS.
Tag for-review was removed from gene: LSS.
Intellectual disability v3.1513 KCNMA1 Arina Puzriakova Tag for-review was removed from gene: KCNMA1.
Intellectual disability v3.1513 H3F3B Arina Puzriakova Tag for-review was removed from gene: H3F3B.
Intellectual disability v3.1513 H3F3A Arina Puzriakova Tag for-review was removed from gene: H3F3A.
Intellectual disability v3.1513 KDM4B Arina Puzriakova Tag for-review was removed from gene: KDM4B.
Intellectual disability v3.1513 BICRA Arina Puzriakova Tag for-review was removed from gene: BICRA.
Intellectual disability v3.1513 ZFHX4 Arina Puzriakova Tag for-review was removed from gene: ZFHX4.
Intellectual disability v3.1513 SHMT2 Arina Puzriakova Tag for-review was removed from gene: SHMT2.
Intellectual disability v3.1513 NARS Arina Puzriakova Tag for-review was removed from gene: NARS.
Intellectual disability v3.1513 MORC2 Arina Puzriakova Tag for-review was removed from gene: MORC2.
Intellectual disability v3.1513 LARS Arina Puzriakova Tag for-review was removed from gene: LARS.
Intellectual disability v3.1513 POLR1C Arina Puzriakova Tag for-review was removed from gene: POLR1C.
Intellectual disability v3.1513 NUS1 Arina Puzriakova Tag for-review was removed from gene: NUS1.
Intellectual disability v3.1513 NUS1 Arina Puzriakova Phenotypes for gene: NUS1 were changed from #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function to Mental retardation, autosomal dominant 55, with seizures, OMIM:617831; Congenital disorder of glycosylation, type 1aa, OMIM:617082
Intellectual disability v3.1512 NUS1 Arina Puzriakova Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.1511 PUM1 Arina Puzriakova Tag for-review was removed from gene: PUM1.
Intellectual disability v3.1511 RALGAPA1 Arina Puzriakova Tag for-review was removed from gene: RALGAPA1.
Intellectual disability v3.1511 RARS Arina Puzriakova Tag for-review was removed from gene: RARS.
Intellectual disability v3.1511 CEP55 Arina Puzriakova Tag for-review was removed from gene: CEP55.
Intellectual disability v3.1511 CTU2 Arina Puzriakova Tag for-review was removed from gene: CTU2.
Intellectual disability v3.1511 TRAPPC4 Arina Puzriakova Tag for-review was removed from gene: TRAPPC4.
Intellectual disability v3.1511 UGP2 Arina Puzriakova Tag for-review was removed from gene: UGP2.
Intellectual disability v3.1511 CXorf56 Arina Puzriakova Tag for-review was removed from gene: CXorf56.
Intellectual disability v3.1511 KAT8 Arina Puzriakova Tag for-review was removed from gene: KAT8.
Intellectual disability v3.1511 SLC5A6 Arina Puzriakova Tag for-review was removed from gene: SLC5A6.
Intellectual disability v3.1511 SNX27 Arina Puzriakova Tag for-review was removed from gene: SNX27.
Intellectual disability v3.1511 WNT1 Arina Puzriakova Tag for-review was removed from gene: WNT1.
Intellectual disability v3.1511 YIF1B Arina Puzriakova Tag for-review was removed from gene: YIF1B.
Intellectual disability v3.1511 VARS2 Arina Puzriakova Tag for-review was removed from gene: VARS2.
Intellectual disability v3.1511 UGDH Arina Puzriakova Tag for-review was removed from gene: UGDH.
Intellectual disability v3.1511 TTC5 Arina Puzriakova Tag for-review was removed from gene: TTC5.
Intellectual disability v3.1511 TRNT1 Arina Puzriakova Tag for-review was removed from gene: TRNT1.
Intellectual disability v3.1511 TNRC6B Arina Puzriakova Tag for-review was removed from gene: TNRC6B.
Intellectual disability v3.1511 TET3 Arina Puzriakova Tag for-review was removed from gene: TET3.
Intellectual disability v3.1511 TENM3 Arina Puzriakova Tag for-review was removed from gene: TENM3.
Intellectual disability v3.1511 TASP1 Arina Puzriakova Tag for-review was removed from gene: TASP1.
Intellectual disability v3.1511 SUZ12 Arina Puzriakova Tag for-review was removed from gene: SUZ12.
Intellectual disability v3.1511 SUPT16H Arina Puzriakova Tag for-review was removed from gene: SUPT16H.
Intellectual disability v3.1511 SPTBN4 Arina Puzriakova Tag for-review was removed from gene: SPTBN4.
Intellectual disability v3.1511 SPOP Arina Puzriakova Tag for-review was removed from gene: SPOP.
Intellectual disability v3.1511 SOX6 Arina Puzriakova Tag for-review was removed from gene: SOX6.
Intellectual disability v3.1511 SLC1A1 Arina Puzriakova Tag for-review was removed from gene: SLC1A1.
Intellectual disability v3.1511 SLC12A2 Arina Puzriakova Tag for-review was removed from gene: SLC12A2.
Intellectual disability v3.1511 SFXN4 Arina Puzriakova Tag for-review was removed from gene: SFXN4.
Intellectual disability v3.1511 SBF1 Arina Puzriakova Tag for-review was removed from gene: SBF1.
Intellectual disability v3.1511 SARS2 Arina Puzriakova Tag for-review was removed from gene: SARS2.
Intellectual disability v3.1511 RSRC1 Arina Puzriakova Tag for-review was removed from gene: RSRC1.
Intellectual disability v3.1511 PPP1R12A Arina Puzriakova Tag for-review was removed from gene: PPP1R12A.
Intellectual disability v3.1511 PIGS Arina Puzriakova Tag for-review was removed from gene: PIGS.
Intellectual disability v3.1511 PIGK Arina Puzriakova Tag for-review was removed from gene: PIGK.
Intellectual disability v3.1511 PIBF1 Arina Puzriakova Tag for-review was removed from gene: PIBF1.
Intellectual disability v3.1511 PDHB Arina Puzriakova Tag for-review was removed from gene: PDHB.
Intellectual disability v3.1511 OXR1 Arina Puzriakova Tag for-review was removed from gene: OXR1.
Intellectual disability v3.1511 NRROS Arina Puzriakova Tag for-review was removed from gene: NRROS.
Intellectual disability v3.1511 NOVA2 Arina Puzriakova Tag for-review was removed from gene: NOVA2.
Intellectual disability v3.1511 NDUFA2 Arina Puzriakova Tag for-review was removed from gene: NDUFA2.
Intellectual disability v3.1511 MTHFS Arina Puzriakova Tag for-review was removed from gene: MTHFS.
Intellectual disability v3.1511 MN1 Arina Puzriakova Tag for-review was removed from gene: MN1.
Intellectual disability v3.1511 LYRM7 Arina Puzriakova Tag for-review was removed from gene: LYRM7.
Intellectual disability v3.1511 LIPT1 Arina Puzriakova Tag for-review was removed from gene: LIPT1.
Intellectual disability v3.1511 KLF7 Arina Puzriakova Tag for-review was removed from gene: KLF7.
Intellectual disability v3.1511 KCNN3 Arina Puzriakova Tag for-review was removed from gene: KCNN3.
Intellectual disability v3.1511 HNRNPH1 Arina Puzriakova Tag for-review was removed from gene: HNRNPH1.
Intellectual disability v3.1511 GPC4 Arina Puzriakova Tag for-review was removed from gene: GPC4.
Intellectual disability v3.1511 GALNT2 Arina Puzriakova Tag for-review was removed from gene: GALNT2.
Intellectual disability v3.1511 EIF2AK2 Arina Puzriakova Tag for-review was removed from gene: EIF2AK2.
Intellectual disability v3.1511 EARS2 Arina Puzriakova Tag for-review was removed from gene: EARS2.
Intellectual disability v3.1511 DNM1L Arina Puzriakova Tag for-review was removed from gene: DNM1L.
Intellectual disability v3.1511 DHX37 Arina Puzriakova Tag for-review was removed from gene: DHX37.
Intellectual disability v3.1511 CNTNAP1 Arina Puzriakova Tag for-review was removed from gene: CNTNAP1.
Intellectual disability v3.1511 B9D2 Arina Puzriakova Tag for-review was removed from gene: B9D2.
Intellectual disability v3.1511 ATAD1 Arina Puzriakova Tag for-review was removed from gene: ATAD1.
Intellectual disability v3.1511 ADD3 Arina Puzriakova Tag for-review was removed from gene: ADD3.
Intellectual disability v3.1511 ADARB1 Arina Puzriakova Tag for-review was removed from gene: ADARB1.
Intellectual disability v3.1511 DLL1 Arina Puzriakova Tag for-review was removed from gene: DLL1.
Intellectual disability v3.1511 RNF113A Arina Puzriakova Tag for-review was removed from gene: RNF113A.
Intellectual disability v3.1511 GAD1 Arina Puzriakova Tag for-review was removed from gene: GAD1.
Intellectual disability v3.1511 ALG9 Arina Puzriakova Tag for-review was removed from gene: ALG9.
Intellectual disability v3.1511 STT3A Arina Puzriakova Tag for-review was removed from gene: STT3A.
Intellectual disability v3.1511 NEDD4L Arina Puzriakova Tag for-review was removed from gene: NEDD4L.
Intellectual disability v3.1511 MADD Arina Puzriakova Mode of inheritance for gene: MADD was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1510 MADD Arina Puzriakova Tag for-review was removed from gene: MADD.
Intellectual disability v3.1510 KDM6B Arina Puzriakova Tag for-review was removed from gene: KDM6B.
Intellectual disability v3.1510 HERC2 Arina Puzriakova Tag for-review was removed from gene: HERC2.
Intellectual disability v3.1510 AHCY Arina Puzriakova Tag for-review was removed from gene: AHCY.
Intellectual disability v3.1510 PIGP Arina Puzriakova Tag for-review was removed from gene: PIGP.
Intellectual disability v3.1510 RNF13 Arina Puzriakova Tag watchlist was removed from gene: RNF13.
Tag for-review was removed from gene: RNF13.
Intellectual disability v3.1510 PTRHD1 Arina Puzriakova Tag for-review was removed from gene: PTRHD1.
Intellectual disability v3.1510 XYLT1 Arina Puzriakova Tag for-review was removed from gene: XYLT1.
Intellectual disability v3.1510 WDFY3 Arina Puzriakova Tag for-review was removed from gene: WDFY3.
Intellectual disability v3.1510 USP7 Arina Puzriakova Tag for-review was removed from gene: USP7.
Intellectual disability v3.1510 TRPM3 Arina Puzriakova Tag watchlist was removed from gene: TRPM3.
Tag for-review was removed from gene: TRPM3.
Intellectual disability v3.1510 NR4A2 Arina Puzriakova Tag watchlist was removed from gene: NR4A2.
Tag for-review was removed from gene: NR4A2.
Intellectual disability v3.1510 CEP104 Arina Puzriakova Tag for-review was removed from gene: CEP104.
Intellectual disability v3.1510 C2CD3 Arina Puzriakova Tag for-review was removed from gene: C2CD3.
Intellectual disability v3.1510 ATP1A2 Arina Puzriakova Tag for-review was removed from gene: ATP1A2.
Intellectual disability v3.1510 ABAT Arina Puzriakova Tag for-review was removed from gene: ABAT.
Intellectual disability v3.1510 TCTN3 Arina Puzriakova Tag for-review was removed from gene: TCTN3.
Intellectual disability v3.1510 TOR1A Arina Puzriakova Tag for-review was removed from gene: TOR1A.
Intellectual disability v3.1510 TANC2 Arina Puzriakova Tag for-review was removed from gene: TANC2.
Intellectual disability v3.1510 ADAM22 Arina Puzriakova Tag for-review was removed from gene: ADAM22.
Intellectual disability v3.1510 UBR7 Arina Puzriakova Tag for-review was removed from gene: UBR7.
Intellectual disability v3.1510 VPS4A Arina Puzriakova Tag for-review was removed from gene: VPS4A.
Intellectual disability v3.1510 RNU7-1 Arina Puzriakova Tag for-review was removed from gene: RNU7-1.
Intellectual disability v3.1510 PPIL1 Arina Puzriakova Tag for-review was removed from gene: PPIL1.
Intellectual disability v3.1510 FBRSL1 Arina Puzriakova Tag for-review was removed from gene: FBRSL1.
Intellectual disability v3.1510 CACNB4 Sarah Leigh commented on gene: CACNB4: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 CNOT3 Sarah Leigh commented on gene: CNOT3: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 ZNF335 Sarah Leigh commented on gene: ZNF335: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 MFSD2A Sarah Leigh commented on gene: MFSD2A: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 MAPRE2 Sarah Leigh commented on gene: MAPRE2: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 SCN1B Sarah Leigh commented on gene: SCN1B
Intellectual disability v3.1510 SCAMP5 Sarah Leigh commented on gene: SCAMP5: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 KAT8 Sarah Leigh commented on gene: KAT8: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 GPC4 Sarah Leigh commented on gene: GPC4: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 KDM6B Sarah Leigh commented on gene: KDM6B: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 CDK19 Sarah Leigh commented on gene: CDK19: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 EXT2 Sarah Leigh commented on gene: EXT2: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 TOR1A Sarah Leigh commented on gene: TOR1A: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 ABCA2 Sarah Leigh commented on gene: ABCA2
Intellectual disability v3.1510 PIGH Sarah Leigh commented on gene: PIGH
Intellectual disability v3.1510 METTL5 Sarah Leigh commented on gene: METTL5
Intellectual disability v3.1510 LMBRD2 Sarah Leigh commented on gene: LMBRD2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 LIAS Sarah Leigh commented on gene: LIAS
Intellectual disability v3.1510 CSNK1G1 Sarah Leigh commented on gene: CSNK1G1
Intellectual disability v3.1510 ALG14 Sarah Leigh commented on gene: ALG14: After NHSGenomic Medicine Service consideration, the rating of this gene has not been changed.
Intellectual disability v3.1510 SLC12A6 Sarah Leigh commented on gene: SLC12A6: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 COG4 Sarah Leigh commented on gene: COG4: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 SCN8A Sarah Leigh commented on gene: SCN8A: Just 2 families reported with possible AR inheritance: v rare - all het parents seem to have features so prob ok to keep as monoallelic only (source NHS Genomic Medicine Service).
Intellectual disability v3.1510 SCN8A Sarah Leigh commented on gene: SCN8A: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 AGO2 Sarah Leigh commented on gene: AGO2: Green rating is for monoallelic MOI only, many cases reported with speech delay and variable ID (source NHS Genomic Medicine Service).
Intellectual disability v3.1510 AGO2 Sarah Leigh commented on gene: AGO2
Intellectual disability v3.1510 PNPT1 Sarah Leigh commented on gene: PNPT1
Intellectual disability v3.1510 SCO1 Sarah Leigh commented on gene: SCO1
Intellectual disability v3.1510 FA2H Sarah Leigh commented on gene: FA2H: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 COX6B1 Sarah Leigh commented on gene: COX6B1
Intellectual disability v3.1510 MPI Sarah Leigh commented on gene: MPI
Intellectual disability v3.1510 VAMP1 Sarah Leigh commented on gene: VAMP1
Intellectual disability v3.1510 TRIM32 Sarah Leigh commented on gene: TRIM32
Intellectual disability v3.1510 MGP Sarah Leigh commented on gene: MGP: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 LGI4 Sarah Leigh commented on gene: LGI4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 HYLS1 Sarah Leigh commented on gene: HYLS1
Intellectual disability v3.1510 HADH Sarah Leigh commented on gene: HADH
Intellectual disability v3.1510 FLVCR1 Sarah Leigh commented on gene: FLVCR1
Intellectual disability v3.1510 ATL1 Sarah Leigh commented on gene: ATL1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 ANKH Sarah Leigh commented on gene: ANKH: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 AFG3L2 Sarah Leigh commented on gene: AFG3L2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 KCNC3 Sarah Leigh commented on gene: KCNC3
Intellectual disability v3.1510 ALKBH8 Sarah Leigh commented on gene: ALKBH8
Intellectual disability v3.1510 SOX3 Sarah Leigh commented on gene: SOX3
Intellectual disability v3.1510 PRKD1 Sarah Leigh commented on gene: PRKD1
Intellectual disability v3.1510 GPSM2 Sarah Leigh commented on gene: GPSM2
Intellectual disability v3.1510 DDOST Sarah Leigh commented on gene: DDOST
Intellectual disability v3.1510 CYP2U1 Sarah Leigh commented on gene: CYP2U1
Intellectual disability v3.1510 AGPS Sarah Leigh commented on gene: AGPS
Intellectual disability v3.1510 TMEM106B Sarah Leigh commented on gene: TMEM106B
Intellectual disability v3.1510 NEMF Sarah Leigh commented on gene: NEMF
Intellectual disability v3.1510 MPP5 Sarah Leigh commented on gene: MPP5
Intellectual disability v3.1510 MAPK1 Sarah Leigh commented on gene: MAPK1
Intellectual disability v3.1510 LMNB1 Sarah Leigh commented on gene: LMNB1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 KIF21B Sarah Leigh commented on gene: KIF21B
Intellectual disability v3.1510 JARID2 Sarah Leigh commented on gene: JARID2
Intellectual disability v3.1510 FAM50A Sarah Leigh commented on gene: FAM50A
Intellectual disability v3.1510 CEP120 Sarah Leigh commented on gene: CEP120
Intellectual disability v3.1510 ZNF526 Sarah Leigh commented on gene: ZNF526
Intellectual disability v3.1510 TFE3 Sarah Leigh commented on gene: TFE3: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 PIGQ Sarah Leigh commented on gene: PIGQ: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 KAT5 Sarah Leigh commented on gene: KAT5
Intellectual disability v3.1510 ZNF335 Sarah Leigh commented on gene: ZNF335
Intellectual disability v3.1510 ZIC1 Sarah Leigh commented on gene: ZIC1
Intellectual disability v3.1510 SETD1A Sarah Leigh commented on gene: SETD1A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 PET100 Sarah Leigh commented on gene: PET100
Intellectual disability v3.1510 NUDT2 Sarah Leigh commented on gene: NUDT2
Intellectual disability v3.1510 MFSD2A Sarah Leigh commented on gene: MFSD2A
Intellectual disability v3.1510 MAPRE2 Sarah Leigh commented on gene: MAPRE2
Intellectual disability v3.1510 CDH2 Sarah Leigh commented on gene: CDH2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SMG8 Sarah Leigh commented on gene: SMG8
Intellectual disability v3.1510 LSS Sarah Leigh commented on gene: LSS
Intellectual disability v3.1510 KCNMA1 Sarah Leigh commented on gene: KCNMA1
Intellectual disability v3.1510 H3F3B Sarah Leigh commented on gene: H3F3B
Intellectual disability v3.1510 H3F3A Sarah Leigh commented on gene: H3F3A
Intellectual disability v3.1510 KDM4B Sarah Leigh commented on gene: KDM4B
Intellectual disability v3.1510 BICRA Sarah Leigh commented on gene: BICRA
Intellectual disability v3.1510 ZFHX4 Sarah Leigh commented on gene: ZFHX4
Intellectual disability v3.1510 SHMT2 Sarah Leigh commented on gene: SHMT2
Intellectual disability v3.1510 NARS Sarah Leigh commented on gene: NARS
Intellectual disability v3.1510 MORC2 Sarah Leigh commented on gene: MORC2
Intellectual disability v3.1510 LARS Sarah Leigh commented on gene: LARS
Intellectual disability v3.1510 POLR1C Sarah Leigh commented on gene: POLR1C
Intellectual disability v3.1510 NUS1 Sarah Leigh commented on gene: NUS1
Intellectual disability v3.1510 PUM1 Sarah Leigh commented on gene: PUM1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 RALGAPA1 Sarah Leigh commented on gene: RALGAPA1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 RARS Sarah Leigh commented on gene: RARS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 CEP55 Sarah Leigh commented on gene: CEP55
Intellectual disability v3.1510 CTU2 Sarah Leigh commented on gene: CTU2
Intellectual disability v3.1510 TRAPPC4 Sarah Leigh commented on gene: TRAPPC4
Intellectual disability v3.1510 UGP2 Sarah Leigh commented on gene: UGP2
Intellectual disability v3.1510 CXorf56 Sarah Leigh commented on gene: CXorf56
Intellectual disability v3.1510 KAT8 Sarah Leigh commented on gene: KAT8
Intellectual disability v3.1510 SLC5A6 Sarah Leigh commented on gene: SLC5A6: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SNX27 Sarah Leigh commented on gene: SNX27: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 WNT1 Sarah Leigh commented on gene: WNT1
Intellectual disability v3.1510 YIF1B Sarah Leigh commented on gene: YIF1B
Intellectual disability v3.1510 VARS2 Sarah Leigh commented on gene: VARS2
Intellectual disability v3.1510 UGDH Sarah Leigh commented on gene: UGDH
Intellectual disability v3.1510 TTC5 Sarah Leigh commented on gene: TTC5: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 TRNT1 Sarah Leigh commented on gene: TRNT1
Intellectual disability v3.1510 TNRC6B Sarah Leigh commented on gene: TNRC6B
Intellectual disability v3.1510 TET3 Sarah Leigh commented on gene: TET3: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 TENM3 Sarah Leigh commented on gene: TENM3
Intellectual disability v3.1510 TASP1 Sarah Leigh commented on gene: TASP1
Intellectual disability v3.1510 SUZ12 Sarah Leigh commented on gene: SUZ12: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SUPT16H Sarah Leigh commented on gene: SUPT16H
Intellectual disability v3.1510 SPTBN4 Sarah Leigh commented on gene: SPTBN4
Intellectual disability v3.1510 SPOP Sarah Leigh commented on gene: SPOP
Intellectual disability v3.1510 SOX6 Sarah Leigh commented on gene: SOX6: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SLC1A1 Sarah Leigh commented on gene: SLC1A1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SLC12A2 Sarah Leigh commented on gene: SLC12A2
Intellectual disability v3.1510 SFXN4 Sarah Leigh commented on gene: SFXN4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SBF1 Sarah Leigh commented on gene: SBF1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SARS2 Sarah Leigh commented on gene: SARS2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 RSRC1 Sarah Leigh commented on gene: RSRC1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 PPP1R12A Sarah Leigh commented on gene: PPP1R12A
Intellectual disability v3.1510 PIGS Sarah Leigh commented on gene: PIGS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 PIGK Sarah Leigh commented on gene: PIGK: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 PIBF1 Sarah Leigh commented on gene: PIBF1
Intellectual disability v3.1510 PDHB Sarah Leigh commented on gene: PDHB
Intellectual disability v3.1510 OXR1 Sarah Leigh commented on gene: OXR1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 NRROS Sarah Leigh commented on gene: NRROS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 NOVA2 Sarah Leigh commented on gene: NOVA2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 NDUFA2 Sarah Leigh commented on gene: NDUFA2
Intellectual disability v3.1510 MTHFS Sarah Leigh commented on gene: MTHFS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 MN1 Sarah Leigh commented on gene: MN1
Intellectual disability v3.1510 LYRM7 Sarah Leigh commented on gene: LYRM7
Intellectual disability v3.1510 LIPT1 Sarah Leigh commented on gene: LIPT1
Intellectual disability v3.1510 KLF7 Sarah Leigh commented on gene: KLF7
Intellectual disability v3.1510 KCNN3 Sarah Leigh commented on gene: KCNN3
Intellectual disability v3.1510 HNRNPH1 Sarah Leigh commented on gene: HNRNPH1
Intellectual disability v3.1510 GPC4 Sarah Leigh commented on gene: GPC4
Intellectual disability v3.1510 GALNT2 Sarah Leigh commented on gene: GALNT2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 EIF2AK2 Sarah Leigh commented on gene: EIF2AK2
Intellectual disability v3.1510 EARS2 Sarah Leigh commented on gene: EARS2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 DNM1L Sarah Leigh commented on gene: DNM1L
Intellectual disability v3.1510 DHX37 Sarah Leigh commented on gene: DHX37
Intellectual disability v3.1510 CTNND1 Sarah Leigh commented on gene: CTNND1
Intellectual disability v3.1510 CNTNAP1 Sarah Leigh commented on gene: CNTNAP1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 B9D2 Sarah Leigh commented on gene: B9D2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 ATAD1 Sarah Leigh commented on gene: ATAD1
Intellectual disability v3.1510 ADD3 Sarah Leigh commented on gene: ADD3
Intellectual disability v3.1510 ADARB1 Sarah Leigh commented on gene: ADARB1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 DLL1 Sarah Leigh commented on gene: DLL1
Intellectual disability v3.1510 RNF113A Sarah Leigh commented on gene: RNF113A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 GAD1 Sarah Leigh commented on gene: GAD1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 ALG9 Sarah Leigh commented on gene: ALG9: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 STT3A Sarah Leigh commented on gene: STT3A
Intellectual disability v3.1510 NEDD4L Sarah Leigh commented on gene: NEDD4L
Intellectual disability v3.1510 MADD Sarah Leigh commented on gene: MADD
Intellectual disability v3.1510 KDM6B Sarah Leigh commented on gene: KDM6B
Intellectual disability v3.1510 HERC2 Sarah Leigh commented on gene: HERC2
Intellectual disability v3.1510 CDK19 Sarah Leigh commented on gene: CDK19: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 AHCY Sarah Leigh commented on gene: AHCY: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 PIGP Sarah Leigh commented on gene: PIGP: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 RNF13 Sarah Leigh commented on gene: RNF13: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 EXT2 Sarah Leigh commented on gene: EXT2
Intellectual disability v3.1510 PTRHD1 Sarah Leigh commented on gene: PTRHD1
Intellectual disability v3.1510 XYLT1 Sarah Leigh commented on gene: XYLT1
Intellectual disability v3.1510 WDFY3 Sarah Leigh commented on gene: WDFY3
Intellectual disability v3.1510 USP7 Sarah Leigh commented on gene: USP7
Intellectual disability v3.1510 TRPM3 Sarah Leigh commented on gene: TRPM3
Intellectual disability v3.1510 NR4A2 Sarah Leigh commented on gene: NR4A2
Intellectual disability v3.1510 CEP104 Sarah Leigh commented on gene: CEP104
Intellectual disability v3.1510 C2CD3 Sarah Leigh commented on gene: C2CD3: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 ATP1A2 Sarah Leigh commented on gene: ATP1A2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 ABAT Sarah Leigh commented on gene: ABAT: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 TCTN3 Sarah Leigh commented on gene: TCTN3
Intellectual disability v3.1510 TOR1A Sarah Leigh commented on gene: TOR1A
Intellectual disability v3.1510 TANC2 Sarah Leigh commented on gene: TANC2
Intellectual disability v3.1510 ADAM22 Sarah Leigh commented on gene: ADAM22: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 UBR7 Sarah Leigh commented on gene: UBR7
Intellectual disability v3.1510 VPS4A Sarah Leigh commented on gene: VPS4A
Intellectual disability v3.1510 RNU7-1 Sarah Leigh commented on gene: RNU7-1
Intellectual disability v3.1510 PPIL1 Sarah Leigh commented on gene: PPIL1
Intellectual disability v3.1510 FBRSL1 Sarah Leigh commented on gene: FBRSL1
Intellectual disability v3.1509 CACNB4 Arina Puzriakova Source NHS GMS was added to CACNB4.
Intellectual disability v3.1509 CNOT3 Arina Puzriakova Source NHS GMS was added to CNOT3.
Intellectual disability v3.1509 ZNF335 Arina Puzriakova Source NHS GMS was added to ZNF335.
Intellectual disability v3.1509 MFSD2A Arina Puzriakova Source NHS GMS was added to MFSD2A.
Intellectual disability v3.1509 MAPRE2 Arina Puzriakova Source NHS GMS was added to MAPRE2.
Intellectual disability v3.1509 SCN1B Arina Puzriakova Source NHS GMS was added to SCN1B.
Intellectual disability v3.1509 SCAMP5 Arina Puzriakova Source NHS GMS was added to SCAMP5.
Intellectual disability v3.1509 KAT8 Arina Puzriakova Source NHS GMS was added to KAT8.
Intellectual disability v3.1509 GPC4 Arina Puzriakova Source NHS GMS was added to GPC4.
Intellectual disability v3.1509 KDM6B Arina Puzriakova Source NHS GMS was added to KDM6B.
Intellectual disability v3.1509 CDK19 Arina Puzriakova Source NHS GMS was added to CDK19.
Intellectual disability v3.1509 EXT2 Arina Puzriakova Source NHS GMS was added to EXT2.
Intellectual disability v3.1509 TOR1A Arina Puzriakova Source NHS GMS was added to TOR1A.
Intellectual disability v3.1509 ABCA2 Arina Puzriakova Source Expert Review Green was added to ABCA2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PIGH Arina Puzriakova Source Expert Review Green was added to PIGH.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 METTL5 Arina Puzriakova Source Expert Review Green was added to METTL5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 LMBRD2 Arina Puzriakova Source Expert Review Green was added to LMBRD2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 LIAS Arina Puzriakova Source Expert Review Green was added to LIAS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 CSNK1G1 Arina Puzriakova Source Expert Review Green was added to CSNK1G1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 AGO2 Arina Puzriakova Source Expert Review Green was added to AGO2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PNPT1 Arina Puzriakova Source Expert Review Green was added to PNPT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SCO1 Arina Puzriakova Source Expert Review Red was added to SCO1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 FA2H Arina Puzriakova Source Expert Review Red was added to FA2H.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 COX6B1 Arina Puzriakova Source Expert Review Red was added to COX6B1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 MPI Arina Puzriakova Source Expert Review Red was added to MPI.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 VAMP1 Arina Puzriakova Source Expert Review Red was added to VAMP1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 TRIM32 Arina Puzriakova Source Expert Review Red was added to TRIM32.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 MGP Arina Puzriakova Source Expert Review Red was added to MGP.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 LGI4 Arina Puzriakova Source Expert Review Red was added to LGI4.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 HYLS1 Arina Puzriakova Source Expert Review Red was added to HYLS1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 HADH Arina Puzriakova Source Expert Review Red was added to HADH.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 FLVCR1 Arina Puzriakova Source Expert Review Red was added to FLVCR1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 ATL1 Arina Puzriakova Source Expert Review Red was added to ATL1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 ANKH Arina Puzriakova Source Expert Review Red was added to ANKH.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 AFG3L2 Arina Puzriakova Source Expert Review Red was added to AFG3L2.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1509 KCNC3 Arina Puzriakova Source Expert Review Amber was added to KCNC3.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1509 ALKBH8 Arina Puzriakova Source Expert Review Amber was added to ALKBH8.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1509 SOX3 Arina Puzriakova Source Expert Review Amber was added to SOX3.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1509 PRKD1 Arina Puzriakova Source Expert Review Amber was added to PRKD1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1509 GPSM2 Arina Puzriakova Source Expert Review Amber was added to GPSM2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1509 DDOST Arina Puzriakova Source Expert Review Amber was added to DDOST.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1509 CYP2U1 Arina Puzriakova Source Expert Review Amber was added to CYP2U1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1509 AGPS Arina Puzriakova Source Expert Review Amber was added to AGPS.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1509 TMEM106B Arina Puzriakova Source Expert Review Green was added to TMEM106B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 NEMF Arina Puzriakova Source Expert Review Green was added to NEMF.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 MPP5 Arina Puzriakova Source Expert Review Green was added to MPP5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 MAPK1 Arina Puzriakova Source Expert Review Green was added to MAPK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 LMNB1 Arina Puzriakova Source Expert Review Green was added to LMNB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 KIF21B Arina Puzriakova Source Expert Review Green was added to KIF21B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 JARID2 Arina Puzriakova Source Expert Review Green was added to JARID2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 FAM50A Arina Puzriakova Source Expert Review Green was added to FAM50A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 CEP120 Arina Puzriakova Source Expert Review Green was added to CEP120.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ZNF526 Arina Puzriakova Source Expert Review Green was added to ZNF526.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TFE3 Arina Puzriakova Source Expert Review Green was added to TFE3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PIGQ Arina Puzriakova Source Expert Review Green was added to PIGQ.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 KAT5 Arina Puzriakova Source Expert Review Green was added to KAT5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ZNF335 Arina Puzriakova Source Expert Review Green was added to ZNF335.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ZIC1 Arina Puzriakova Source Expert Review Green was added to ZIC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SETD1A Arina Puzriakova Source Expert Review Green was added to SETD1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PET100 Arina Puzriakova Source Expert Review Green was added to PET100.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 NUDT2 Arina Puzriakova Source Expert Review Green was added to NUDT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 MFSD2A Arina Puzriakova Source Expert Review Green was added to MFSD2A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 MAPRE2 Arina Puzriakova Source Expert Review Green was added to MAPRE2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 CDH2 Arina Puzriakova Source Expert Review Green was added to CDH2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SMG8 Arina Puzriakova Source Expert Review Green was added to SMG8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 LSS Arina Puzriakova Source Expert Review Green was added to LSS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 KCNMA1 Arina Puzriakova Source Expert Review Green was added to KCNMA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 H3F3B Arina Puzriakova Source Expert Review Green was added to H3F3B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 H3F3A Arina Puzriakova Source Expert Review Green was added to H3F3A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 KDM4B Arina Puzriakova Source Expert Review Green was added to KDM4B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 BICRA Arina Puzriakova Source Expert Review Green was added to BICRA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ZFHX4 Arina Puzriakova Source Expert Review Green was added to ZFHX4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SHMT2 Arina Puzriakova Source Expert Review Green was added to SHMT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 NARS Arina Puzriakova Source Expert Review Green was added to NARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 MORC2 Arina Puzriakova Source Expert Review Green was added to MORC2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 LARS Arina Puzriakova Source Expert Review Green was added to LARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 POLR1C Arina Puzriakova Source Expert Review Green was added to POLR1C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 NUS1 Arina Puzriakova Source Expert Review Green was added to NUS1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PUM1 Arina Puzriakova Source Expert Review Green was added to PUM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 RALGAPA1 Arina Puzriakova Source Expert Review Green was added to RALGAPA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 RARS Arina Puzriakova Source Expert Review Green was added to RARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 CEP55 Arina Puzriakova Source Expert Review Green was added to CEP55.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 CTU2 Arina Puzriakova Source Expert Review Green was added to CTU2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TRAPPC4 Arina Puzriakova Source Expert Review Green was added to TRAPPC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 UGP2 Arina Puzriakova Source Expert Review Green was added to UGP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 CXorf56 Arina Puzriakova Source Expert Review Green was added to CXorf56.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 KAT8 Arina Puzriakova Source Expert Review Green was added to KAT8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SLC5A6 Arina Puzriakova Source Expert Review Green was added to SLC5A6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SNX27 Arina Puzriakova Source Expert Review Green was added to SNX27.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 WNT1 Arina Puzriakova Source Expert Review Green was added to WNT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 YIF1B Arina Puzriakova Source Expert Review Green was added to YIF1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 VARS2 Arina Puzriakova Source Expert Review Green was added to VARS2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 UGDH Arina Puzriakova Source Expert Review Green was added to UGDH.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TTC5 Arina Puzriakova Source Expert Review Green was added to TTC5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TRNT1 Arina Puzriakova Source Expert Review Green was added to TRNT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TNRC6B Arina Puzriakova Source Expert Review Green was added to TNRC6B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TET3 Arina Puzriakova Source Expert Review Green was added to TET3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TENM3 Arina Puzriakova Source Expert Review Green was added to TENM3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TASP1 Arina Puzriakova Source Expert Review Green was added to TASP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SUZ12 Arina Puzriakova Source Expert Review Green was added to SUZ12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SUPT16H Arina Puzriakova Source Expert Review Green was added to SUPT16H.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SPTBN4 Arina Puzriakova Source Expert Review Green was added to SPTBN4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SPOP Arina Puzriakova Source Expert Review Green was added to SPOP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SOX6 Arina Puzriakova Source Expert Review Green was added to SOX6.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SLC1A1 Arina Puzriakova Source Expert Review Green was added to SLC1A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SLC12A2 Arina Puzriakova Source Expert Review Green was added to SLC12A2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SFXN4 Arina Puzriakova Source Expert Review Green was added to SFXN4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SBF1 Arina Puzriakova Source Expert Review Green was added to SBF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 SARS2 Arina Puzriakova Source Expert Review Green was added to SARS2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 RSRC1 Arina Puzriakova Source Expert Review Green was added to RSRC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PPP1R12A Arina Puzriakova Source Expert Review Green was added to PPP1R12A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PIGS Arina Puzriakova Source Expert Review Green was added to PIGS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PIGK Arina Puzriakova Source Expert Review Green was added to PIGK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PIBF1 Arina Puzriakova Source Expert Review Green was added to PIBF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PDHB Arina Puzriakova Source Expert Review Green was added to PDHB.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 OXR1 Arina Puzriakova Source Expert Review Green was added to OXR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 NRROS Arina Puzriakova Source Expert Review Green was added to NRROS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 NOVA2 Arina Puzriakova Source Expert Review Green was added to NOVA2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 NDUFA2 Arina Puzriakova Source Expert Review Green was added to NDUFA2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 MTHFS Arina Puzriakova Source Expert Review Green was added to MTHFS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 MN1 Arina Puzriakova Source Expert Review Green was added to MN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 LYRM7 Arina Puzriakova Source Expert Review Green was added to LYRM7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 LIPT1 Arina Puzriakova Source Expert Review Green was added to LIPT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 KLF7 Arina Puzriakova Source Expert Review Green was added to KLF7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 KCNN3 Arina Puzriakova Source Expert Review Green was added to KCNN3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 HNRNPH1 Arina Puzriakova Source Expert Review Green was added to HNRNPH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 GPC4 Arina Puzriakova Source Expert Review Green was added to GPC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 GALNT2 Arina Puzriakova Source Expert Review Green was added to GALNT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 EIF2AK2 Arina Puzriakova Source Expert Review Green was added to EIF2AK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 EARS2 Arina Puzriakova Source Expert Review Green was added to EARS2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 DNM1L Arina Puzriakova Source Expert Review Green was added to DNM1L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 DHX37 Arina Puzriakova Source Expert Review Green was added to DHX37.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 CTNND1 Arina Puzriakova Source Expert Review Green was added to CTNND1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 CNTNAP1 Arina Puzriakova Source Expert Review Green was added to CNTNAP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 B9D2 Arina Puzriakova Source Expert Review Green was added to B9D2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ATAD1 Arina Puzriakova Source Expert Review Green was added to ATAD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ADD3 Arina Puzriakova Source Expert Review Green was added to ADD3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ADARB1 Arina Puzriakova Source Expert Review Green was added to ADARB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 DLL1 Arina Puzriakova Source Expert Review Green was added to DLL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 RNF113A Arina Puzriakova Source Expert Review Green was added to RNF113A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 GAD1 Arina Puzriakova Source Expert Review Green was added to GAD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ALG9 Arina Puzriakova Source Expert Review Green was added to ALG9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 STT3A Arina Puzriakova Source Expert Review Green was added to STT3A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 NEDD4L Arina Puzriakova Source Expert Review Green was added to NEDD4L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 MADD Arina Puzriakova Source Expert Review Green was added to MADD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 KDM6B Arina Puzriakova Source Expert Review Green was added to KDM6B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 HERC2 Arina Puzriakova Source Expert Review Green was added to HERC2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 CDK19 Arina Puzriakova Source Expert Review Green was added to CDK19.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 AHCY Arina Puzriakova Source Expert Review Green was added to AHCY.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PIGP Arina Puzriakova Source Expert Review Green was added to PIGP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 RNF13 Arina Puzriakova Source Expert Review Green was added to RNF13.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 EXT2 Arina Puzriakova Source Expert Review Green was added to EXT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PTRHD1 Arina Puzriakova Source Expert Review Green was added to PTRHD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 XYLT1 Arina Puzriakova Source Expert Review Green was added to XYLT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 WDFY3 Arina Puzriakova Source Expert Review Green was added to WDFY3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 USP7 Arina Puzriakova Source Expert Review Green was added to USP7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TRPM3 Arina Puzriakova Source Expert Review Green was added to TRPM3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 NR4A2 Arina Puzriakova Source Expert Review Green was added to NR4A2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 CEP104 Arina Puzriakova Source Expert Review Green was added to CEP104.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 C2CD3 Arina Puzriakova Source Expert Review Green was added to C2CD3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ATP1A2 Arina Puzriakova Source Expert Review Green was added to ATP1A2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ABAT Arina Puzriakova Source Expert Review Green was added to ABAT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TCTN3 Arina Puzriakova Source Expert Review Green was added to TCTN3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TOR1A Arina Puzriakova Source Expert Review Green was added to TOR1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 TANC2 Arina Puzriakova Source Expert Review Green was added to TANC2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 ADAM22 Arina Puzriakova Source Expert Review Green was added to ADAM22.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 UBR7 Arina Puzriakova Source Expert Review Green was added to UBR7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 VPS4A Arina Puzriakova Source Expert Review Green was added to VPS4A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 RNU7-1 Arina Puzriakova Source Expert Review Green was added to RNU7-1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 PPIL1 Arina Puzriakova Source Expert Review Green was added to PPIL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1509 FBRSL1 Arina Puzriakova Source Expert Review Green was added to FBRSL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1508 MAT1A Arina Puzriakova commented on gene: MAT1A
Intellectual disability v3.1508 GJC2 Arina Puzriakova commented on gene: GJC2
Intellectual disability v3.1507 MAT1A Arina Puzriakova Mode of inheritance for gene MAT1A was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1507 GJC2 Arina Puzriakova Mode of inheritance for gene GJC2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1506 PDZD8 Konstantinos Varvagiannis changed review comment from: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene.

Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula.

Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [* -also to consider for MOI]Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family.

Previous genetic testing was not reported.

Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above).

The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES.

Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B).

Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz).

Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon).

PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided).

The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood.

The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology.

Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia.

Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports.
Sources: Literature; to: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene.

Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula.

Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [*] (also to consider for MOI) : Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family.

Previous genetic testing was not reported.

Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above).

The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES.

Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B).

Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz).

Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon).

PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided).

The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood.

The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology.

Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia.

Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports.
Sources: Literature
Intellectual disability v3.1506 PDZD8 Konstantinos Varvagiannis gene: PDZD8 was added
gene: PDZD8 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDZD8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDZD8 were set to 35227461
Phenotypes for gene: PDZD8 were set to Global developmental delay; Intellectual disability; Autistic behavior; Behavioral abnormality; Myopathy; Abnormality of the face; Hypertelorism; Seizures; Disproportionate tall stature
Penetrance for gene: PDZD8 were set to Complete
Review for gene: PDZD8 was set to AMBER
Added comment: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene.

Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula.

Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [* -also to consider for MOI]Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family.

Previous genetic testing was not reported.

Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above).

The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES.

Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B).

Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz).

Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon).

PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided).

The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood.

The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology.

Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia.

Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports.
Sources: Literature
Intellectual disability v3.1506 POU1F1 Arina Puzriakova Phenotypes for gene: POU1F1 were changed from Gene2Phenotype confirmed gene with ID HPO to Pituitary hormone deficiency, combined or isolated, 1, OMIM:613038
Intellectual disability v3.1505 POU1F1 Arina Puzriakova Mode of inheritance for gene: POU1F1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1504 KCNE1 Arina Puzriakova Mode of inheritance for gene: KCNE1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1503 KCNE1 Arina Puzriakova Phenotypes for gene: KCNE1 were changed from NA to Jervell and Lange-Nielsen syndrome 2, OMIM:612347; Long QT syndrome 5, OMIM:613695
Intellectual disability v3.1502 HSF4 Arina Puzriakova Phenotypes for gene: HSF4 were changed from Cataract 5, multiple types, 116800 to Cataract 5, multiple types, OMIM:116800
Intellectual disability v3.1501 NALCN Arina Puzriakova Phenotypes for gene: NALCN were changed from ?Neuroaxonal neurodegeneration, infantile, with facial dysmophism, 615419; CONGENITAL CONTRACTURES OF THE LIMBS AND FACE, HYPOTONIA, AND DEVELOPMENTAL DELAY to Congenital contractures of the limbs and face, hypotonia, and developmental delay, OMIM:616266; Hypotonia, infantile, with psychomotor retardation and characteristic facies 1, OMIM:615419
Intellectual disability v3.1500 CHKA Konstantinos Varvagiannis gene: CHKA was added
gene: CHKA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHKA were set to 35202461
Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature
Penetrance for gene: CHKA were set to Complete
Review for gene: CHKA was set to GREEN
Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants.

Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6.

Eventual previous genetic testing was not discussed.

Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies.

Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype.

3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2):
- c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families],
- c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents],
- c.2T>C/p.(Met1?) [1 hmz individual born to related parents],
- c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual.

CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes.

CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP.

As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants].

Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc.

CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect.

In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine).

Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively).

NMD is thought to underly the deleterious effect of the frameshift one (not studied).

The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein.

Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714).

There is no associated phenotype in OMIM, Gene2Phenotype or SysID.

Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset).
Sources: Literature
Intellectual disability v3.1500 FGFR2 Arina Puzriakova Mode of inheritance for gene: FGFR2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1499 FGFR2 Arina Puzriakova Tag Q1_22_MOI was removed from gene: FGFR2.
Intellectual disability v3.1499 FGFR2 Arina Puzriakova Tag Q1_22_MOI tag was added to gene: FGFR2.
Intellectual disability v3.1499 POLR1D Arina Puzriakova Phenotypes for gene: POLR1D were changed from Treacher Collins syndrome 2, 613717 to Treacher Collins syndrome 2, OMIM:613717
Intellectual disability v3.1498 POLR1D Arina Puzriakova Mode of inheritance for gene: POLR1D was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1497 GJC2 Arina Puzriakova Phenotypes for gene: GJC2 were changed from Leukodystrophy, hypomyelinating, 2, 608804Spastic paraplegia 44, autosomal recessive, 613206Lymphedema, hereditary, IC, 613480; LYMPHEDEMA, HEREDITARY, IC to Leukodystrophy, hypomyelinating, 2, OMIM:608804
Intellectual disability v3.1496 PRKAR1B Zornitza Stark reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33833410; Phenotypes: Marbach-Schaaf neurodevelopmental syndrome MIM#619680; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1496 SLC35F1 Zornitza Stark gene: SLC35F1 was added
gene: SLC35F1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SLC35F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC35F1 were set to 33821533
Phenotypes for gene: SLC35F1 were set to Neruodevelopmental disorder, MONDO:0700092, SLC35F1-associated; Rett-like syndrome
Review for gene: SLC35F1 was set to RED
Added comment: WES identified a de novo heterozygous c.1037T>C; p.(I346T) (absent in gnomad v2 and v3) in a female described to have Rett-like syndrome.

Global developmental delay, generalized tonic andtonic–clonic seizure, never acquired independent walking and developed spastictetraplegia in adulthood and limited speech

No functional data
Sources: Literature
Intellectual disability v3.1496 CSTF2 Zornitza Stark reviewed gene: CSTF2: Rating: AMBER; Mode of pathogenicity: None; Publications: 32816001; Phenotypes: Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1496 SPRED2 Ivone Leong Tag Q1_22_rating tag was added to gene: SPRED2.
Intellectual disability v3.1496 SPRED2 Ivone Leong Classified gene: SPRED2 as Amber List (moderate evidence)
Intellectual disability v3.1496 SPRED2 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 (Strong) but not in OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1496 SPRED2 Ivone Leong Gene: spred2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1496 SPRED2 Ivone Leong Classified gene: SPRED2 as Amber List (moderate evidence)
Intellectual disability v3.1496 SPRED2 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 (Strong) but not in OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1496 SPRED2 Ivone Leong Gene: spred2 has been classified as Amber List (Moderate Evidence).
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.
-----
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; Chan