Open AccessAssessing the role of rare genetic variants in drug‐resistant, non‐lesional focal epilepsy
Author(s) -
Wolking Stefan,
Moreau Claudia,
McCormack Mark,
Krause Roland,
Krenn Martin,
Berkovic Samuel,
Cavalleri Gianpiero L.,
Delanty Norman,
Depondt Chantal,
Johnson Michael R.,
Koeleman Bobby P. C.,
Kunz Wolfram S.,
Lerche Holger,
Marson Anthony G.,
O’Brien Terence J.,
Petrovski Slave,
Sander Josemir W.,
Sills Graeme J.,
Striano Pasquale,
Zara Federico,
Zimprich Fritz,
Sisodiya Sanjay M.,
Girard Simon L.,
Cossette Patrick
Publication year - 2021
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.51374
Subject(s) - medicine , epilepsy , exome sequencing , drug resistant epilepsy , candidate gene , gene , drug resistance , epilepsy syndromes , drug , cohort , exome , bioinformatics , genetics , mutation , biology , pharmacology , psychiatry
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.