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Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

外显子组测序 外显子组 癫痫 遗传学 癫痫综合征 队列 错义突变 γ-氨基丁酸受体 医学 生物 生物信息学 突变 内科学 基因 受体 精神科
作者
Patrick May,Simon L. Girard,Merle Harrer,Dheeraj Reddy Bobbili,Julian Schubert,Stefan Wolking,Felicitas Becker,Pamela Lachance-Touchette,Caroline Meloche,Micheline Gravel,Cristina Elena Niturad,Julia Knaus,Carolien G.F. de Kovel,Mohamad Toliat,Anne Polvi,Michele Iacomino,Rosa Guerrero,Stéphanie Baulac,Carla Marini,Holger Thiele,Janine Altmüller,Kamel Jabbari,Ann-Kathrin Ruppert,Wiktor Jurkowski,Dennis Lal,Raffaella Rusconi,Sandrine Cestèle,Benedetta Terragni,Ian D. Coombs,Christopher A. Reid,Pasquale Striano,Hande Çağlayan,Auli Sirén,Kate V. Everett,Rikke S. Møller,Helle Hjalgrim,Hiltrud Muhle,Ingo Helbig,Wolfram S. Kunz,Yvonne G. Weber,Sarah Weckhuysen,Peter De Jonghe,Sanjay M. Sisodiya,Rima Nabbout,Silvana Franceschetti,Giangennaro Coppola,Maria Stella Vari,Dorothee Kasteleijn–Nolst Trenité,Betül Baykan,Uğur Özbek,Nerses Bebek,Karl Martin Klein,Felix Rosenow,Dang Khoa Nguyen,François Dubeau,Lionel Carmant,Anne Lortie,Richard Desbiens,Jean‐François Clément,Cécile Cieuta‐Walti,Graeme J. Sills,Pauls Auce,Ben Francis,Michael R. Johnson,Anthony G Marson,Bianca Berghuis,Josemir W. Sander,Andreja Avberšek,Mark McCormack,Gianpiero L. Cavalleri,Norman Delanty,Chantal Depondt,Martin Krenn,Fritz Zimprich,Sarah Peter,Marina Nikanorova,Robert Kraaij,Jeroen van Rooij,Rudi Balling,M. Arfan Ikram,André G. Uitterlinden,G. Avanzini,Stephanie Schorge,Steven Petrou,Massimo Mantegazza,Thomas Sander,Eric LeGuern,Joan Serratosa,Bobby P. C. Koeleman,Aarno Palotie,Anna‐Elina Lehesjoki,Michael Nothnagel,Peter Nürnberg,Snezana Maljevic,Federico Zara,Patrick Cossette,Roland Krause,Holger Lerche,Patrick May,Simon L. Girard
出处
期刊:Lancet Neurology [Elsevier BV]
卷期号:17 (8): 699-708 被引量:67
标识
DOI:10.1016/s1474-4422(18)30215-1
摘要

Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).
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