ATP1A1

Inheritance Pattern: AD

Disease ID:MONDO:0020788

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0054833

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0054833

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0054833

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0020788

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0020788

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0054833

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0020788

Submitter: Illumina

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.

Inheritance Pattern: AD

Disease ID:MONDO:0054833

Submitter: ClinGen

ATP1A1 was first described in the context of autosomal dominant, axonal or intermediate Charcot-Marie-Tooth (CMT) disease, when Lassuthova et al. identified seven unrelated families with co-segregating or de-novo heterozygous point mutations (PMID: 29499166). Further intermediate neuropathy patients were reported by He et al. (PMID: 31373411) and Argente-Escrig et al. (PMID: 34323022), expanding the genotype spectrum to a number of 10 published pathogenic neuropathy variants as of August 2022. In parallel, ATP1A1 has been associated with renal hypomagnesemia and hypokalemia (PMID: 30388404), and several other variants have been reported in association with a complex phenotype involving distal weakness and spasticity, intellectual disability, hyperactivity, and seizures, partially with, but mainly without serum electrolyte disturbances (PMIDs: 35110381, 32277047, 33968856). ATP1A1 encodes the catalytic α1-subunit of the ATP-dependent sodium-potassium pump that is responsible for the stabilization of the electrochemical gradient over cell membranes. Sodium-potassium ATPases are ubiquitously expressed, however, the α1-subunit has a particularly high expression in the nervous system (PMID: 29499166). Functional studies on variants described in CMT patientsdemonstrated a reduced protein stability in transfected HeLa cells (PMID: 31373411) and a reduced cell viability under ATPase inhibitory ouabain treatment in transfected U2OS cells (PMID: 29499166). Similarly, two-electrode voltage clamp recordings showed reduced currents in transfected Xenopus cells compared to wildtype (PMID: 29499166). Based on gene and regional constraint (GnomAD), ATP1A1 is considered highly intolerant to haploinsufficiency, which is in accordance with the autosomal dominant inheritance. So far, it is not known how specific missense mutations cause one and not another associated phenotype. In a linear protein model, no regional clusters have been identified (PMID: 35110381). There is currently no further experimental evidence explaining how nerves are damaged specifically. It is possible that ATP1A1 mutation carriers with intellectual disability, spasticity, and/or seizures show (milder) signs of neuropathy as well, which might, however, retreat in the background of their more severe syndrome (PMID: 35110381, 32277047, 33968856). With a summed LOD score of 11.21 and the absence of such variants in healthy control collectives, we classify the gene-disease relationship of ATP1A1 and autosomal dominant, axonal and intermediate CMT as moderate. Further cases yet to be published and the expected replication over time will most likely increase the evidence score to a definitive level soon. **Recuration Update:** Three additional families from two publications were curated, providing new genetic and functional evidence supporting the association between ATP1A1 and autosomal dominant Charcot-Marie-Tooth disease. Yuksel et al. (2023; PMID: 36738336) reported a novel heterozygous ATP1A1 c.1799C>G (p.Pro600Arg) variant in a patient with early-onset demyelinating Charcot-Marie-Tooth disease. Multiple pathogenic missense variants associated with CMT cluster within the transmembrane helices surrounding residue 600, supporting this region as a mutational hotspot. In addition, a different pathogenic substitution at Pro600 was already associated with ATP1A1 neuropathy, supporting the importance of this residue. The variant was absent in the unaffected sibling and was supported by extensive functional studies demonstrating reduced ATP1A1 protein expression, decreased Na⁺/K⁺-ATPase activity in Xenopus oocytes, and impaired cell viability in an ouabain-rescue assay, consistent with loss of pump function. This case and its functional data contributed additional genetic evidence to the gene-disease relationship. Based on the phenotype, variant evidence, and functional data, this proband was scored as 1.0 point for genetic evidence. Spontarelli Fruit et al. (2025; PMID: 41048924) described two unrelated individuals with intermediate Charcot-Marie-Tooth disease carrying the recurrent ATP1A1 c.1645G>A (p.Gly549Arg) variant, confirmed to have arisen de novo in both patients. The study also provided complementary functional evidence demonstrating impaired Na⁺/K⁺-ATPase activity by electrophysiology, abnormal plasma membrane localization, and reduced cellular survival, further supporting the pathogenic mechanism of ATP1A1 variants. Each unrelated family was scored as 1.0 point, contributing a total of 2.0 genetic evidence points. Together, these publications added new independent case-level evidence, including confirmed de novo occurrences, and additional variant-specific functional evidence, increasing the total genetic evidence score to 12.5 points, thereby supporting an upgrade of the ATP1A1–Charcot-Marie-Tooth disease gene-disease **relationship from Moderate to Definitive.**

Inheritance Pattern: AD

Disease ID:MONDO:0054833

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0020788

Submitter: G2P