Severe microcephaly

Gene: ATP6V0A1

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 3 p.m. | Last Modified: 1 Feb 2023, 3 p.m.

Panel Version: 3.5

Green List (high evidence)

None of the biallelic cases reported by PMID: 34909687, exhibited microcephaly as a result of this, biallelic mode of inheritance has not been included for ATP6V0A1 on the Severe microcephaly panel.

Created: 30 Jun 2022, 8:37 a.m. | Last Modified: 30 Jun 2022, 8:37 a.m.

Panel Version: 2.305

Comment on phenotypes: Phenotype from Gen2Phen https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4422

Created: 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
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

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

• PMID: 34909687

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

I don't know

PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio developmental disorder study. 11 de novo missense identified in ~10,000 cases with developmental disorders (no other phenotype info provided hence Amber rating).
PMID: 30842224 - identified a de novo missense variant in a single individual with atypical Rett syndrome phenotype
Sources: Literature

Created: 3 Nov 2020, 11:01 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Developmental disorder; Rett syndrome-like

Publications

• 30842224
• 33057194