Objective: 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. Methods: 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. Results: 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. Interpretation: 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.
Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy / Wolking, S.; Moreau, C.; Mccormack, M.; Krause, R.; Krenn, M.; Berkovic, S.; Cavalleri, G. L.; Delanty, N.; Depondt, C.; Johnson, M. R.; Koeleman, B. P. C.; Kunz, W. S.; Lerche, H.; Marson, A. G.; O'Brien, T. J.; Petrovski, S.; Sander, J. W.; Sills, G. J.; Striano, P.; Zara, F.; Zimprich, F.; Sisodiya, S. M.; Girard, S. L.; Cossette, P.; Avbersek, A.; Leu, C.; Heggeli, K.; Demurtas, R.; Willis, J.; Speed, D.; Sargsyan, N.; Chinthapalli, K.; Borghei, M.; Coppola, A.; Gambardella, A.; Becker, F.; Rau, S.; Hengsbach, C.; Weber, Y. G.; Berghuis, B.; Campbell, E.; Gudmundsson, L. J.; Ingason, A.; Stefansson, K.; Schneider, R.; Balling, R.; Auce, P.; Francis, B.; Jorgensen, A.; Morris, A.; Langley, S.; Srivastava, P.; Brodie, M.; Todaro, M.; Hutton, J.; Muhle, H.; Klein, K. M.; Moller, R. S.; Nikanorova, M.; Weckhuysen, S.; Rener-Primec, Z.; Craig, J.; Stefansson, H.. - In: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY. - ISSN 2328-9503. - 8:7(2021), pp. 1376-1387. [10.1002/acn3.51374]
Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy
Krause R.;Striano P.;Coppola A.;Schneider R.;
2021
Abstract
Objective: 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. Methods: 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. Results: 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. Interpretation: 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
