De novo variants inKCNJ3are associated with early-onset epilepsy

Abstract

BackgroundKCNJ3encodes a subunit of G-protein-coupled inwardly rectifying potassium channels, which are important for cellular excitability and inhibitory neurotransmission. However, the genetic basis ofKCNJ3in epilepsy has not been determined. This study aimed to identify the pathogenicKCNJ3variants in patients with epilepsy.MethodsTrio exome sequencing was performed to determine potential variants of epilepsy. Individuals withKCNJ3variants were recruited for this study. Detailed clinical information and genetic data were obtained and systematically reviewed. Whole-cell patch-clamp recordings were performed to evaluate the functional consequences of the identified variants.ResultsTwo de novo missense variants (c.998T>C (p.Leu333Ser) and c.938G>A (p. Arg313Gln)) inKCNJ3were identified in two unrelated families with epilepsy. The variants were absent from the gnomAD database and were assumed to be damaging or probably damaging using multiple bioinformatics tools. They were both located in the C‐terminal domain. The amino acid residues were highly conserved among various species. Clinically, the seizures occurred at a young age and were under control after combined treatment. Electrophysiological analysis revealed that theKCNJ3Leu333Ser and Arg313Gln variants significantly compromised the current activities and exhibited loss-of-function (LOF) effects.ConclusionOur findings suggest that de novo LOF variants inKCNJ3are associated with early-onset epilepsy. Genetic testing ofKCNJ3in patients with epilepsy may serve as a strategy for precision medicine.