Genetic Landscape of <b><i>SCN1A</i></b> Variants in a Turkish Cohort with GEFS+ Spectrum and Dravet Syndrome

Abstract

<b><i>Introduction:</i></b> The α subunit of voltage-gated sodium channels in mammals is encoded by 9 different genes, and variations in the <i>SCN1A</i>, <i>SCN2A</i>, <i>SCN3A</i>, and <i>SCN8A</i> genes highly expressed in the CNS have been associated with epilepsy phenotypes. This study aimed at investigating the frequency of <i>SCN1A</i> gene variations in Dravet syndrome (DS) and GEFS+ spectrum phenotype cases and discussing the molecular results in the context of genotype-phenotype correlation. <b><i>Methods:</i></b> Fifteen patients diagnosed with DS and 54 patients meeting the GEFS+ spectrum criteria were included in this study. All patients were evaluated by next-generation sequencing and multiplex ligation-dependent probe amplification using an <i>SCN1A</i> gene commercial kit. <b><i>Results:</i></b> A total of 17 different variants were detected in 18 index cases (26%), of which 7 were novel variations (p.M1R, p.M147T, p.I767L, p.N1391Ifs*5, p.R1886G, p.E1915G, p.R1933Q). Of the 18 cases with variation in the <i>SCN1A</i> gene, 12 had DS and 6 had GEFS+ phenotype. The variations were de novo in all DS cases and in 1 case with a GEFS+ phenotype; in 5 GEFS+ cases, the variant was inherited from the affected parent. <b><i>Discussion:</i></b> This study contributes to the variation spectrum in cases with DS and GEFS+ phenotype with the novel variants detected. <i>SCN1A</i> genetic analysis can help in determining whether antiseizure medication should be selected or avoided in cases with variations. The elucidation of the molecular etiology makes it possible to provide the family with effective genetic counseling for future pregnancies.