De novo heterozygous missense variants inATP11Aare associated with refractory focal epilepsy

Background ATP11A encodes an integral-membrane type IV P-type-adenosine triphosphatase that plays an important role in neural development by maintaining membrane lipid asymmetry. ATP11A de novo heterozygous missense variants have been reported to be associated with hypomyelinating leukodystrophy; however, the neurological symptoms of patients are often varying. In this study, we aimed to explore the relationship between ATP11A variants and epilepsy. Methods Trio-based whole-exome sequencing was performed on patients with focal epilepsy. Multiple bioinformatics analyses were used to predict the pathogenicity of the variants. Previously reported literature was collected to analyse the relation between variants and phenotypes. Results Two de novo heterozygous missense variants of ATP11A were identified in two unrelated patients with refractory focal epilepsy and were predicted to be pathogenic using multiple bioinformatics analyses. Then, six patients associated with missense variants were collected. Half of the patients (3/6) with variants located on/near the transmembrane regions (TMs) had more severe and multiple neurological symptoms, while the other half with non-TM variants had mild and single symptoms, indicating a correlation between variant location and phenotype. All patients showed progressively worsening conditions, potentially due to a gradually increased expression of ATP11A in the human brain over time. Conclusion This study suggested that de novo heterozygous missense variants of ATP11A are associated with refractory focal epilepsy. Missense variant-associated phenotypes range from epileptic seizures to severe neurological symptoms. It should be noted that patients with ATP11A variants have a gradually worsening potential.