Intellectual disability - microarray and sequencing
Gene: ATP6V0A1
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Removed the Q3_22_MOI tag as the MOI has been proposed to be Monoallelic by all reviewersCreated: 11 Oct 2022, 1:18 p.m. | Last Modified: 11 Oct 2022, 1:18 p.m.
Panel Version: 3.1742
Comment on phenotypes: Phenotype from Gen2Phen https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4422Created: 28 Jun 2022, 5:11 p.m. | Last Modified: 28 Jun 2022, 5:11 p.m.
Panel Version: 3.1614
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).Created: 28 Jun 2022, 5:08 p.m. | Last Modified: 28 Jun 2022, 5:08 p.m.
Panel Version: 3.1612
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.Created: 28 Jun 2022, 4:16 p.m. | Last Modified: 28 Jun 2022, 5:03 p.m.
Panel Version: 3.1612
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 28 Jun 2022, 3:22 p.m. | Last Modified: 28 Jun 2022, 3:22 p.m.
Panel Version: 3.1610
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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.Created: 22 Jun 2022, 11:48 a.m. | Last Modified: 22 Jun 2022, 12:12 p.m.
Panel Version: 3.1606
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications
Mode of pathogenicity
Other
Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.Created: 4 Dec 2020, 2:15 p.m. | Last Modified: 4 Dec 2020, 2:15 p.m.
Panel Version: 3.579
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 11 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
PMID: 30842224 - identified a de novo missense variant in a single individual with atypical Rett syndrome phenotype
Sources: LiteratureCreated: 3 Nov 2020, 11:01 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Developmental disorder; Rett syndrome-like
Publications
Tag Q3_22_rating was removed from gene: ATP6V0A1. Tag Q3_22_NHS_review was removed from gene: ATP6V0A1.
Source NHS GMS was added to ATP6V0A1. Source Expert Review Green was added to ATP6V0A1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q3_22_MOI was removed from gene: ATP6V0A1.
Phenotypes for gene: ATP6V0A1 were changed from ATP6V0A1-related developmental disorder (monoallelic) to ATP6V0A1-related developmental disorder (monoallelic)
Phenotypes for gene: ATP6V0A1 were changed from Developmental disorder; Rett syndrome-like to ATP6V0A1-related developmental disorder (monoallelic)
Tag Q3_22_MOI tag was added to gene: ATP6V0A1.
Publications for gene: ATP6V0A1 were set to 30842224; 33057194; 34909687
Mode of inheritance for gene: ATP6V0A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
Tag Q3_22_rating tag was added to gene: ATP6V0A1. Tag Q3_22_NHS_review tag was added to gene: ATP6V0A1.
Publications for gene: ATP6V0A1 were set to 30842224; 33057194
Gene: atp6v0a1 has been classified as Amber List (Moderate Evidence).
gene: ATP6V0A1 was added gene: ATP6V0A1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ATP6V0A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATP6V0A1 were set to 30842224; 33057194 Phenotypes for gene: ATP6V0A1 were set to Developmental disorder; Rett syndrome-like Review for gene: ATP6V0A1 was set to AMBER