Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome
Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome
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DOI：
10.1093/hmg/ddv036
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发表时间：
2015-05-15
影响因子：
3.5
通讯作者：
Redon, Richard
中科院分区：
文献类型：
--
作者：
Le Scouarnec, Solena;Karakachoff, Matilde;Redon, Richard
Brugada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有关。在20-30%的病例中，SCN 5A基因突变与BrS有因果关系。其他20个基因已被描述为与BrS有关，但它们对疾病患病率的总体贡献仍不清楚。本研究的目的是估计在一个大的BrS患者群体中，罕见的结核病易感基因编码变异的负担。我们已经开发了一个定制的试剂盒，捕获和序列的编码区的45个先前报道的疟疾易感基因，并将此试剂盒应用于167个索引的情况下，提出了一个Brugada模式的心电图，以及167个人年龄超过65岁，没有心律失常的历史。通过应用负荷检验，仅观察到SCN 5A的罕见编码变异（次要等位基因频率低于0.1%）显著富集，BrS病例中20.4%携带罕见编码变异，对照个体中2.4%携带罕见编码变异（P = 1.4 x 10（-7））。未观察到任何其他疟疾易感基因（包括SCN 10A和CACNA 1C）的显著富集。这些结果表明，除了SCN 5A，罕见的编码变异，在以前报道的疟疾易感基因没有显着贡献的发生BrS在欧洲血统的人口。因此，在分子诊断环境中解释遗传变异时应格外小心，因为对于大多数先前报道的BrS易感基因，在病例与对照组之间观察到的罕见编码变异程度相似。
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 x 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.