Le Scouarnec Solena, Karakachoff Matilde, Gourraud Jean-Baptiste, Lindenbaum Pierre, Bonnaud Stéphanie, Portero Vincent, Duboscq-Bidot Laëtitia, Daumy Xavier, Simonet Floriane, Teusan Raluca, Baron Estelle, Violleau Jade, Persyn Elodie, Bellanger Lise, Barc Julien, Chatel Stéphanie, Martins Raphaël, Mabo Philippe, Sacher Frédéric, Haïssaguerre Michel, Kyndt Florence, Schmitt Sébastien, Bézieau Stéphane, Le Marec Hervé, Dina Christian, Schott Jean-Jacques, Probst Vincent, Redon Richard
Inserm, UMR 1087, l'institut du thorax, Nantes, France, CNRS, UMR 6291, Nantes, France, Université de Nantes, Nantes, France.
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.
Hum Mol Genet. 2015 May 15;24(10):2757-63. doi: 10.1093/hmg/ddv036. Epub 2015 Feb 3.
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.
布加综合征（BrS）是一种罕见的遗传性心律失常疾病，与心室颤动和心源性猝死相关。SCN5A基因突变在20%-30%的病例中与布加综合征存在因果关系。另外20个基因已被描述与布加综合征有关，但它们对疾病患病率的总体贡献仍不清楚。本研究旨在评估一大群布加综合征患者中心律失常易感基因的罕见编码变异负担。我们开发了一种定制试剂盒，用于捕获和测序45个先前报道的心律失常易感基因的编码区，并将该试剂盒应用于167例心电图呈现布加综合征模式的索引病例以及167名65岁以上且无心律失常病史的个体。通过应用负担测试，仅在SCN5A基因中观察到罕见编码变异有显著富集（次要等位基因频率低于0.1%），20.4%的布加综合征病例携带罕见编码变异，而对照个体中这一比例为2.4%（P = 1.4×10⁻⁷）。对于任何其他心律失常易感基因，包括SCN10A和CACNA1C，均未观察到显著富集。这些结果表明，除SCN5A外，先前报道的心律失常易感基因中的罕见编码变异对欧洲血统人群中布加综合征的发生没有显著贡献。因此，在分子诊断环境中解释基因变异时应格外谨慎，因为对于大多数先前报道的布加综合征易感基因，病例和对照中观察到的罕见编码变异程度相似。
