Submission Details

Autosomal dominant

07/31/2019

The ATP1A1 gene was first reported in relation to autosomal dominant ATP1A1-related hypomagnesemia, seizures, and intellectual disability in 2018 (30388404: Schlingmann et al. 2018). De novo missense variants in the ATP1A1 gene were observed in three individuals with a syndromic form of intellectual disability (30388404: Schlingmann et al. 2018). Specifically, these individuals showed an early onset hypomagnesemia and seizure phenotype with global developmental delay. Two of the cases also presented with autism spectrum disorder. In addition, a de novo splice site variant in the ATP1A1 gene was identified in an individual with autism spectrum disorder (25363768: Iossifov et al. 2014). ATP1A1 is an alpha subunit of Na+/K+ ATPase which is expressed ubiquitously throughout the brain in both neurons and glia and Na+/K+ ATPase is essential for the regulation of extracellular K+ levels during neuronal activity. Na+/K+ ATPase is composed of a catalytic alpha subunit isoform and an accessory beta subunit isoform, the combination of the two subunit isoforms determines the kinetic characteristics of the enzyme (27148079: Larsen et al. 2016). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Of note, variants in the ATP1A1 gene have also been associated with an autosomal dominant form of Charcot Marie Tooth disease (29499166: Lassuthova et al. 2018). The individuals described did not have intellectual disability, all variants were inherited, and the phenotype is different from those described Schlingmann et al. (2018).. This condition was therefore not curated.

30388404 27148079