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

Wolking, Stefan, Moreau, Claudia, McCormack, Mark, Krause, Roland, Krenn, Martin, Berkovic, Samuel, Cavalleri, Gianpiero L, Delanty, Norman, Depondt, Chantal, Johnson, Michael R
et al (show 14 more authors) (2021) Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy. ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, 8 (7). pp. 1376-1387.

Access the full-text of this item by clicking on the Open Access link.


<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Interpretation</h4>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.

Item Type: Article
Uncontrolled Keywords: EpiPGx Consortium, Humans, Cohort Studies, Polymorphism, Single Nucleotide, Female, Male, Genetic Variation, Genetic Association Studies, Drug Resistant Epilepsy, Exome Sequencing
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Population Health
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 07 Dec 2021 10:24
Last Modified: 08 Feb 2023 16:59
DOI: 10.1002/acn3.51374
Open Access URL:
Related URLs: