title: Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome.
abstract: The Brugada syndrome (BrS) is a rare heritable cardiac arrhythmia disorder associated with ventricular fibrillation and sudden cardiac death. Mutations in the SCN5A gene have been causally related to BrS in 20-30% of cases. Twenty other genes have been described as involved in BrS, but their overall contribution to disease prevalence is still unclear. This study aims to estimate the burden of rare coding variation in arrhythmia-susceptibility genes among a large group of patients with BrS. We have developed a custom kit to capture and sequence the coding regions of 45 previously reported arrhythmia-susceptibility genes and applied this kit to 167 index cases presenting with a Brugada pattern on the electrocardiogram as well as 167 individuals aged over 65-year old and showing no history of cardiac arrhythmia. By applying burden tests, a significant enrichment in rare coding variation (with a minor allele frequency below 0.1%) was observed only for SCN5A, with rare coding variants carried by 20.4% of cases with BrS versus 2.4% of control individuals (P = 1.4 × 10(-7)). No significant enrichment was observed for any other arrhythmia-susceptibility gene, including SCN10A and CACNA1C. These results indicate that, except for SCN5A, rare coding variation in previously reported arrhythmia-susceptibility genes do not contribute significantly to the occurrence of BrS in a population with European ancestry. Extreme caution should thus be taken when interpreting genetic variation in molecular diagnostic setting, since rare coding variants were observed in a similar extent among cases versus controls, for most previously reported BrS-susceptibility genes.
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France.
authors: Solena
authors: S
authors: Le Scouarnec
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, Institute of Clinical Physiology, National Research Council, Pisa, Italy.
authors: Matilde
authors: M
authors: Karakachoff
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors: Jean-Baptiste
authors: JB
authors: Gourraud
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors: Pierre
authors: P
authors: Lindenbaum
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors: Stéphanie
authors: S
authors: Bonnaud
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France.
authors: Vincent
authors: V
authors: Portero
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France.
authors: Laëtitia
authors: L
authors: Duboscq-Bidot
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France.
authors: Xavier
authors: X
authors: Daumy
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France.
authors: Floriane
authors: F
authors: Simonet
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France.
authors: Raluca
authors: R
authors: Teusan
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France.
authors: Estelle
authors: E
authors: Baron
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors: Jade
authors: J
authors: Violleau
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France.
authors: Elodie
authors: E
authors: Persyn
authors: Université de Nantes, Nantes, France, Laboratoire de Mathématiques Jean Leray, UMR CNRS 6629, Nantes, France.
authors: Lise
authors: L
authors: Bellanger
authors: Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
authors: Julien
authors: J
authors: Barc
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors: Stéphanie
authors: S
authors: Chatel
authors: CHU Rennes, Service de Cardiologie, France.
authors: Raphaël
authors: R
authors: Martins
authors: CHU Rennes, Service de Cardiologie, France.
authors: Philippe
authors: P
authors: Mabo
authors: CHU Bordeaux, Service de Cardiologie, LYRIC Institute, France and.
authors: Frédéric
authors: F
authors: Sacher
authors: CHU Bordeaux, Service de Cardiologie, LYRIC Institute, France and.
authors: Michel
authors: M
authors: Haïssaguerre
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors: Florence
authors: F
authors: Kyndt
authors: Université de Nantes, Nantes, France, CHU Nantes, Service de Génétique Médicale, Nantes, France.
authors: Sébastien
authors: S
authors: Schmitt
authors: Université de Nantes, Nantes, France, CHU Nantes, Service de Génétique Médicale, Nantes, France.
authors: Stéphane
authors: S
authors: Bézieau
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors: Hervé
authors: H
authors: Le Marec
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors: Christian
authors: C
authors: Dina
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors: Jean-Jacques
authors: JJ
authors: Schott
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors: Vincent
authors: V
authors: Probst
authors: Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France, CHU Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France, richard.redon@inserm.fr.
authors: Richard
authors: R
authors: Redon
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics; D053840:Brugada Syndrome / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005796:Genes; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D017422:Sequence Analysis, DNA; D044465:White People
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human