Previously defined variants of uncertain significance may play an important role in epilepsy and interactions between certain variants may become pathogenic

Abstract

Epilepsy is a chronic neurological disorder characterized by recurrent seizures and associated neurological, cognitive, psychological, and social effects. The prevalence of active epilepsy is estimated to be between 4-10 per 1000 individuals in the general population, with the highest incidence occurring during infancy and childhood. Genetic mutations play a significant role in epilepsy, and over 500 genes have been associated with the condition. Next-Generation Sequencing (NGS) panels are utilized for genetic testing, but a substantial proportion of results remain uncertain and are not considered directly causative of epilepsy. In this study, we reevaluated a subgroup of patients with inconclusive variant findings or multiple Variants of Uncertain Significance (VUSs) in their test results. We identified two unrelated variants c.2133G>C in SCN9A and c.316G>A in QARS1 to be potentially pathogenic variants. Additionally, we identified a frequent genetic combination, the RANBP2&RYR3 being prominent among other possible combinations. The RANBP2 gene consistently co-occurred with RYR3 variants in uncertain results, suggesting potential pathogenicity. We also analyzed unaffected parents' data and observed certain combinations inherited from different parents, raising the possibility of specific gene combinations as risk factors for the disease.