ATPase, Na+/K+ Transporting, Alpha-2 Polypeptide (ATP1A2; MIM#182340) is a subunit of a P-type cation transport ATPase integral for establishing and maintaining electrochemical gradients of Na and K across the plasma membrane. Single heterozygous pathogenic variants in ATP1A2 are definitively associated with “hemiplegic migraine-developmental and epileptic encephalopathy spectrum” (MONDO:0100539) as curated by the Epilepsy GCEP of ClinGen.
Biallelic variants in ATP1A2 were first reported by Chatron, et.al., in 2019 in four neonates from two independent families with shared phenotypes of congenital microcephaly, CNS anomalies, and fetal akinesia sequence [PMID:31608932]. Since its initial report, biallelic ATP1A2 variants have been reported in 7 additional probands from 5 independent families with prenatal phenotypes including elevated nuchal translucency or nuchal thickening, microcephaly, polyhydramnios, hydrops, fetal growth restriction, fetal akinesia, dysmorphic features including hypertelorism and micrognathia, and CNS anomalies including polymicrogyria or other abnormalities of gyration, calcifications, and ventriculomegaly [PMID:31608932, 30690204, 37870493, 39046620, 38549198]. Neonatal seizures and neonatal demise due to respiratory insufficiency is also often observed in neonates with biallelic ATP1A2 variants. The presumed mechanism of disease is loss of function with affected probands harboring biallelic nonsense, frameshift, or canonical splice variants with only a single missense variant reported at the time of curation. Maximum genetic evidence of 12.0 points was reached based on literature evidence. Of note, several parents of probands with bialleic ATP1A2 variants reported history of migraines [PMID:31608932, 30690204, 37870493]. Functional evidence including biochemical function [PMID:12763872] and mouse models recapitulating the observed human phenotype [PMID:12805306, 15564586] were scored for an additional 2.5 points. Given this and its replication in the literature over time, ATP1A2 has been curated as Definitive for fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (MONDO:0859204) by the Prenatal Gene Curation Expert Panel (Gene-Disease Validity Standard Operating Procedures, Version 11) on 6/17/2025.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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