Wolking, Stefan; Moreau, Claudia; McCormack, Mark; Krause, Roland; Krenn, Martin; Berkovic, Samuel F; Cavalleri, Gianpiero L; Delanty, Norman; 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

doi:10.1002/acn3.51374

Author(s)

Wolking, Stefan

Moreau, Claudia

McCormack, Mark

Krause, Roland

Krenn, Martin

Berkovic, Samuel F

Cavalleri, Gianpiero L

Delanty, Norman

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

Publication Date

2021-07

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.

Citation

Annals of Clinical and Translational Neurology 2021; 8(7): 1376-1387

Jornal Title

Annals of Clinical and Translational Neurology

OrcId

0000-0002-1460-6623

0000-0002-8213-6141

0000-0001-9938-7126

0000-0003-3026-3082

0000-0003-4580-841X

Link

https://ahro.austin.org.au/austinjspui/handle/1/28668

Title

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

Type of document

Journal Article

Austin Health

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

Files:

Author(s)	Wolking, Stefan Moreau, Claudia McCormack, Mark Krause, Roland Krenn, Martin Berkovic, Samuel F Cavalleri, Gianpiero L Delanty, Norman 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
Publication Date	2021-07
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.
Citation	Annals of Clinical and Translational Neurology 2021; 8(7): 1376-1387
Jornal Title	Annals of Clinical and Translational Neurology
OrcId	0000-0002-1460-6623 0000-0002-8213-6141 0000-0001-9938-7126 0000-0003-3026-3082 0000-0003-4580-841X
Link	https://ahro.austin.org.au/austinjspui/handle/1/28668
Title	Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy.
Type of document	Journal Article