Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy.
Journal
Annals of clinical and translational neurology
ISSN: 2328-9503
Titre abrégé: Ann Clin Transl Neurol
Pays: United States
ID NLM: 101623278
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
08
03
2021
received:
19
12
2020
accepted:
14
04
2021
pubmed:
22
5
2021
medline:
19
1
2022
entrez:
21
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34018700
doi: 10.1002/acn3.51374
pmc: PMC8283173
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1376-1387Subventions
Organisme : Medical Research Council
ID : MR/S02638X/1
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Références
Brain. 2014 Mar;137(Pt 3):795-805
pubmed: 24468822
Brain. 2009 Apr;132(Pt 4):989-98
pubmed: 19153149
Epilepsia. 2019 Jun;60(6):1091-1103
pubmed: 31074842
Epilepsia. 2020 Apr;61(4):657-666
pubmed: 32141622
Cold Spring Harb Perspect Med. 2015 May 01;5(5):a022392
pubmed: 25934463
Epilepsy Curr. 2005 May-Jun;5(3):107-12
pubmed: 16145617
Brain. 2013 Oct;136(Pt 10):3140-50
pubmed: 24014518
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Ann Neurol. 2015 Apr;77(4):675-83
pubmed: 25623524
Ann Neurol. 2017 Mar;81(3):444-453
pubmed: 28165634
Ann Neurol. 2014 May;75(5):788-92
pubmed: 24591017
Epilepsia Open. 2019 Sep 25;4(4):563-571
pubmed: 31819912
J Med Genet. 2017 Jul;54(7):460-470
pubmed: 28377535
Ann Neurol. 2014 May;75(5):782-7
pubmed: 24585383
Epilepsy Res. 2007 Jul;75(2-3):192-6
pubmed: 17628429
Epilepsia. 2015 Oct;56(10):e168-71
pubmed: 26216793
Brain. 2019 Nov 1;142(11):3473-3481
pubmed: 31608925
Pharmacogenomics. 2020 Apr;21(5):325-335
pubmed: 32308125
Nat Genet. 2013 May;45(5):546-51
pubmed: 23542697
Ann Neurol. 1998 Apr;43(4):435-45
pubmed: 9546323
Ann Neurol. 2014 Jan;75(1):147-54
pubmed: 24272827
JAMA Neurol. 2018 Mar 1;75(3):279-286
pubmed: 29279892
Genet Med. 2019 Feb;21(2):398-408
pubmed: 30093711
Lancet Neurol. 2020 Sep;19(9):748-757
pubmed: 32822635
Neurology. 1982 Feb;32(2):174-9
pubmed: 7198743
Neurotherapeutics. 2014 Apr;11(2):324-33
pubmed: 24566939
Epilepsia. 2013 May;54 Suppl 2:41-7
pubmed: 23646970
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Neurology. 2017 Jan 17;88(3):296-303
pubmed: 27986877
J Pharmacol Exp Ther. 2002 Apr;301(1):7-14
pubmed: 11907151
Nat Commun. 2018 Dec 10;9(1):5269
pubmed: 30531953
Epilepsia. 2017 Apr;58(4):512-521
pubmed: 28276062
Cell Rep. 2016 Feb 2;14(4):808-822
pubmed: 26776509
Epilepsia. 2013 May;54 Suppl 2:33-40
pubmed: 23646969
Mol Biol Evol. 2020 Jan 1;37(1):2-10
pubmed: 31504792
Lancet Neurol. 2017 Feb;16(2):135-143
pubmed: 28102150
Epilepsia. 2010 Jun;51(6):1069-77
pubmed: 19889013
Nat Genet. 2006 Aug;38(8):904-9
pubmed: 16862161