Royal College of Surgeons in Ireland
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Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

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journal contribution
posted on 2021-07-05, 09:56 authored by Stefan Wolking, Claudia Moreau, Mark McCormack, Roland Krause, Martin Krenn, EpiPGX Consortium, Samuel Berkovic, Gianpiero CavalleriGianpiero Cavalleri, Norman DelantyNorman Delanty, Chantal Depondt, Michael R Johnson, Bobby PC Koeleman, Wolfram S Kunz, Holger Lerche, Anthony G Marson, Terence J O’Brien, Slave Petrovski, Josemir W Sander, Graeme J Sills, Pasquale Striano, Federico Zara, Fritz Zimprich, Sanjay M Sisodiya, Simon L Girard, Patrick Cossette

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)



The original article is available at

Published Citation

Wolking S. et al. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy. Ann Clin Transl Neurol. 2021;8(7):1376-1387.

Publication Date

21 May 2021

PubMed ID



  • Beaumont Hospital
  • FutureNeuro Centre
  • School of Pharmacy and Biomolecular Sciences




  • Published Version (Version of Record)