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

Annals of Clinical and Translational Neurology - Tập 8 Số 7 - Trang 1376-1387 - 2021
Stefan Wolking1,2,3,4, Claudia Moreau5,3, Mark McCormack6, Roland Krause7, Martin Krenn8, Samuel F. Berkovic9,10, Gianpiero L. Cavalleri11,12,13, Norman Delanty11,14,13, Chantal Depondt15, Michael R. Johnson12, Bobby P.C. Koeleman16, Wolfram S. Kunz17, Holger Lerche2, Anthony G Marson18,19,20, Terence J. O’Brien21,22, Slavé Petrovski23, Josemir W. Sander24,25,26, Graeme J. Sills27, Pasquale Striano28,29, Federico Zara28,30, Fritz Zimprich8, Sanjay M. Sisodiya24,25, Simon Girard5, Patrick Cossette4
1Department of Epileptology and Neurology, University of Aachen, Aachen, Germany
2Neurology and Epileptology Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany
3These authors contributed equally
4Université de Montréal, Montreal, Canada
5Centre Intersectoriel en Santé Durable Université du Québec à Chicoutimi Saguenay Canada
6Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
7Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
8Department of Neurology, Medical University of Vienna, Vienna, Austria
9Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Melbourne, Australia
10Department of Neurology, Austin Health, Heidelberg, Australia
11Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
12Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK
13FutureNeuro Research Centre, Science Foundation Ireland, Dublin, Ireland
14Division of Neurology, Beaumont Hospital, Dublin, Ireland
15Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
16Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
17Institute of Experimental Epileptology and Cognition Research and Department of Epileptology, University of Bonn, Bonn, Germany
18Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
19Liverpool Health Partners, Liverpool, UK
20The Walton Centre NHS Foundation Trust, Liverpool, UK
21Departments of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
22Departments of Neuroscience and Neurology, The Central Clinical School, Monash University and The Alfred Hospital, Melbourne, Australia
23Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D AstraZeneca Cambridge UK
24Chalfont Centre for Epilepsy, Chalfont-St-Peter, UK
25Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK
26Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands
27School of Life Sciences, University of Glasgow, Glasgow, UK
28Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy
29Pediatric Neurology and Muscular Diseases Unit, IRCCS "G. Gaslini" Institute, Genova, Italy
30Laboratory of Neurogenetics and Neuroscience, IRCCS "G. Gaslini" Institute, Genova, Italy

Tóm tắt

AbstractObjectiveResistance 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.MethodsWe 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.ResultsWe 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.InterpretationOur 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.

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Annals of Clinical and Translational Neurology

Tập 8 Số 7

1376-1387

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