Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy
Objective: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance.
Methods: We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE.
Results: We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes - among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE.
Interpretation: Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings.
Genome Canada and Genome Quebec
FP7 grant 279062 “EpiPGX” from the European Commission
German Research Foundation (DFG) (WO 2385/1-1)
CommentsThe original article is available at https://onlinelibrary.wiley.com
Published CitationWolking S et al. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy. Ann Clin Transl Neurol. 2021.
Publication Date21 May 2021
- Beaumont Hospital
- FutureNeuro Centre
- School of Pharmacy and Biomolecular Sciences
- Published Version (Version of Record)