Clinical heterogeneity of epilepsy and mutation spectrum of voltage-gated sodium channel genes

Abstract

Abstract Mutations in the genes encoding voltage-gated sodium channels (Nav) family members are the most frequent cause of epilepsy. This study aims to screen Nav genes (SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, and SCN9A) to identify the sequence variations underlying epileptic phenotypes, including seizures, epileptic encephalopathies, and developmental delays. In this retrospective analysis, medical records of 1526 epilepsy patients were reviewed to extract all the patients who had the following genetic testing done: whole exome sequencing (WES), any next-generation sequencing (NGS) panel, and targeted single-gene testing were used to analyze the patients' genomic DNA sequences. Bioinformatics analysis was performed to analyze and detect the effect of variants on protein structure and stability. Sequence data analysis identified 25 heterozygous variants (4 protein-truncating variants and 21 missense variants) in SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, and SCN9A genes, many of them are novel. Recurrent variants in SCN3A (c.2350A>G) and SCN9A (c.279A>C, c.1482G>T) in multiple individuals were also identified. Several therapeutic drugs, including bromide, phenytoin, oxcarbazepine, valproic acid, and ethosuximide were suggested based on Nav variants identified, which indicates a possible personalized therapeutic approach. Novel variants identified in this work add to the mutation continuum of the Nav genes in the epilepsy phenotype. Moreover, our findings emphasize the wide range of symptoms associated with variants in genes encoding Nav channels, as well as the potential for personalized genomics and personalized therapies.