De novo heterozygous missense variants in <i>ATP11A</i> are associated with refractory focal epilepsy.

Abstract

<i>ATP11A</i> encodes an integral-membrane type IV P-type-adenosine triphosphatase that plays an important role in neural development by maintaining membrane lipid asymmetry. <i>ATP11A</i> 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 <i>ATP11A</i> variants and epilepsy. 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. Two de novo heterozygous missense variants of <i>ATP11A</i> 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 <i>ATP11A</i> in the human brain over time. This study suggested that de novo heterozygous missense variants of <i>ATP11A</i> 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 <i>ATP11A</i> variants have a gradually worsening potential.