PubMed 25650408

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Automatically associated channels: Cav1.2 , Nav1.5 , Nav1.8

Title: Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome.

Authors: Solena Le Scouarnec, Matilde Karakachoff, Jean-Baptiste Gourraud, Pierre Lindenbaum, Stéphanie Bonnaud, Vincent Portero, Laëtitia Duboscq-Bidot, Xavier Daumy, Floriane Simonet, Raluca Teusan, Estelle Baron, Jade Violleau, Elodie Persyn, Lise Bellanger, Julien Barc, Stéphanie Chatel, Raphaël Martins, Philippe Mabo, Frederic Sacher, Michel Haïssaguerre, Florence Kyndt, Sebastien Schmitt, Stéphane Bézieau, Hervé Le Marec, Christian Dina, Jean-Jacques Schott, Vincent Probst, Richard Redon

Journal, date & volume: Hum. Mol. Genet., 2015 May 15 , 24, 2757-63

PubMed link:

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.