Exploring the Genetic Etiology of Drug-Resistant Epilepsy: Incorporation of Exome Sequencing Into Practice Publisher Pubmed



Mahdiannasser M¹ ; Rashidinezhad A^{2, 3} ; Badv RS⁴ ; Akrami SM¹ Show Affiliations
Source: Acta Neurologica Belgica Published:2022

Abstract

Background: By affecting about 50 million people worldwide, epilepsy is considered a global concern in neurology. Intolerable enough, up to ¼ of all patients do not respond to antiepileptic drugs and have recurring seizures. Therefore, revealing the underlying etiology is quite demanding in a clinical context to improve diagnosis and disease management. Methods: Initially, 85 patients suspected of epilepsy underwent thorough clinical and paraclinical evaluation and 24 individuals with drug-resistant epilepsy entered the study. Using whole-exome sequencing, the genetic etiology of drug-resistant epilepsy was investigated and discerned whether this method could facilitate the management of drug-resistant epilepsy through personalized medicine. Eventually, functional annotation was performed and drug–gene interaction networks were constructed to find potential therapeutic targets. Results: We found eleven novel variants in various genes including IRF2BPL, ST3GAL3, and GPAA1, for which a few epilepsy-related variants are available in public databases. The overall diagnostic yield for likely pathogenic and pathogenic variants and the detection rate of novel variants were 25% and 84.6%, respectively. Based on the results, two patients were considered potential candidates for personalized medicine. The highest number of interaction with drugs was demonstrated for SCN1A, SCN2A, and GRIN2A genes. Conclusions: This study highlighted the importance of consanguineous marriage in drug-resistant epilepsy and suggested the possibility of reduced penetrance and variable expressivity in some of the autosomal dominant cases. We also suggest that whole-exome sequencing could facilitate personalized management of drug-resistant epilepsy. Regarding drug–gene interactions, some genes such as SCN1A and SCN2A might serve as therapeutic targets in drug-resistant epilepsy. © 2022, The Author(s) under exclusive licence to Belgian Neurological Society.