Early onset or syndromic epilepsy

Gene: ATP6V1A

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD infantile or early childhood epileptic encephalopathy 3 - delayed psychomotor development, early onset refractory seizures and ID. Fassio et al, 2018 - 4 unrelated patients aged 8-14 with early onset epileptic encephalopathy. Patients of Italian, Mexican, Turkish and Japanese descent. 4 diff de novo het missense variants idenitifed In vitro expression studies done in 2 of these - support pathogenicity.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Cutis laxa, type IID, 617403; Epileptic encephalopathy, infantile or early childhood, 618012

Publications

• 29668857

Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least 4 variants were identified in unrelated cases of Epileptic encephalopathy, infantile or early childhood, 3 618012, one variant (c.1045G>A, NM_001690.3, p.D349N) appear give gain of function results in in vitro analysis, whereas the others had loss of function. Two homozygous variants were reported in two unrelated cases of Cutis laxa, autosomal recessive, type IID 617403 who both had seizures as part of their phenotypes.

Created: 18 Nov 2018, 10:49 p.m.

Comment on phenotypes: Monoallelic variants associated with Epileptic encephalopathy, infantile or early childhood, 3 618012 and biallelic variants associated with Cutis laxa, autosomal recessive, type IID 617403. Both phenotypes include seizures.

Created: 18 Nov 2018, 10:44 p.m.

Green List (high evidence)

Heterozygous mutations in ATP6V1A cause Epileptic encephalopathy, infantile or early childhood, type 3 (MIM 618012).

PMID: 29668857 reports on 4 individuals from 4 families with de novo pathogenic variants in ATP6V1A. The phenotype was consistent with a developmental encephalopathy with epilepsy.

All patients were found to harbor missense variants. The variants resulted in altered lysosomal homeostasis, abnormal neuritogenesis and synaptic density. However in one of the variants tested (p.Asp100Tyr) pathogenicity was mediated by loss-of-function mechanism while for another (p.Asp349Asn) by gain-of-function mechanism.

Differences in severity were noted, with two variants (incl. Asp100Tyr) being associated with a more severe phenotype and the two other (incl. Asp349Asn) with milder degrees of ID and epilepsy.

Biallelic ATP6V1A mutations cause Cutis laxa type IID (MIM 617403). PMID: 28065471 is the first report on 3 individuals from 3 different families (2 of which were consanguineous). All patients were homozygous for ATP6V1A pathogenic variants. All three presented with hypotonia, one (or possibly two) with developmental delay and two with seizures although the developmental phenotype is not further commented on. (Additional patients described in the article harbored mutations in other genes and were not considered).

As a result, this gene can be considered for inclusion in this panel as green.
Sources: Literature, Expert Review

Created: 17 Nov 2018, 7:53 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
# 618012 EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 3 - IECEE3; # 617403 CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IID - ARCL2D

Publications

• 29668857
• 28065471