Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/26547
Title: Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy.
Austin Authors: Wolking, Stefan;Moreau, Claudia;McCormack, Mark;Krause, Roland;Krenn, Martin;Berkovic, Samuel F ;Cavalleri, Gianpiero L;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
Affiliation: Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
Laboratory of Neurogenetics and Neuroscience, IRCCS "G. Gaslini" Institute, Genova, Italy
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy
Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
Centre Intersectoriel en Santé Durable, Université du Québec à Chicoutimi, Saguenay, Canada
Chalfont Centre for Epilepsy, Chalfont-St-Peter, UK
Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK
School of Life Sciences, University of Glasgow, Glasgow, UK
Liverpool Health Partners, Liverpool, UK
Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
The Walton Centre NHS Foundation Trust, Liverpool, UK
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
FutureNeuro Research Centre, Science Foundation Ireland, Dublin, Ireland
Division of Neurology, Beaumont Hospital, Dublin, Ireland..
Université de Montréal, Montreal, Canada
Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Department of Epileptology and Neurology, University of Aachen, Aachen, Germany
Institute of Experimental Epileptology and Cognition Research and Department of Epileptology, University of Bonn, Bonn, Germany
Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Melbourne, Australia
Neurology
Departments of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
Departments of Neuroscience and Neurology, The Central Clinical School, Monash University and The Alfred Hospital, Melbourne, Australia
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy
Pediatric Neurology and Muscular Diseases Unit, IRCCS "G. Gaslini" Institute, Genova, Italy
Chalfont Centre for Epilepsy, Chalfont-St-Peter, UK
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland..
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg..
Department of Neurology, Medical University of Vienna, Vienna, Austria..
Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium..
Department of Neurology, Medical University of Vienna, Vienna, Austria..
Issue Date: 21-May-2021
metadata.dc.date: 2021
Publication information: Annals of Clinical and Translational Neurology 2021; online first: 21 May
Abstract: 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. 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. 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. 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/26547
DOI: 10.1002/acn3.51374
ORCID: 0000-0002-1460-6623
0000-0002-8213-6141
0000-0001-9938-7126
0000-0003-3026-3082
0000-0003-4580-841X
Journal: Annals of Clinical and Translational Neurology
PubMed URL: 34018700
Type: Journal Article
Appears in Collections:Journal articles

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