Whole-exome sequencing identifies Y1495X of SCN5A to be associated with familial conduction disease and sudden death.
Whole-exome sequencing identifies Y1495X of SCN5A to be associated with familial conduction disease and sudden death.
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全外显子组测序发现 SCN5A 的 Y1495X 与家族性传导病和猝死有关
DOI：
10.1038/srep05616
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发表时间：
2014-07-10
影响因子：
4.6
通讯作者：
Yang YF
中科院分区：
文献类型：
--
作者：
Tan ZP;Xie L;Deng Y;Chen JL;Zhang WZ;Wang J;Yang JF;Yang YF
SCN5A突变已被报道为多种遗传性心律失常的基础，而复杂的重叠表型，特别是先天性心脏病（CHD），很少报道。这位48岁的先证者最近在休息时晕厥。超声心动图和超声心动图检查显示冠心病（法洛四联症）和传导疾病。我们结合全外显子组测序（WES）和生物信息学策略，以确定这种常染色体显性心脏传导疾病（CCD）的多代家系的致病基因。我们检查了这个家庭的四个成员，包括三个受影响的和一个未受影响的。在SCN5A中发现了一种新的无义突变（Y1495X）。预测该突变产生截短的SCN 5A蛋白，其可导致钠电流丧失，这是SCN 5A相关心律失常的确定机制。我们的研究提供了证据表明，WES是一种非常有效的方法，用于罕见临床表型的遗传分析。我们的研究还为那些临床呈阴性的亲属提供了准确的基因检测信息。
SCN5A mutations have been reported to underlie a variety of inherited arrhythmias, while the complex overlapping phenotype, especially with congenital heart disease (CHD), is rarely reported. The 48-year-old proband underwent a recent syncope during rest. A CHD (tetralogy of Fallot) and conduction disease was revealed by echocardiogram and ultrasonic cardiogram examination. We combined whole-exome sequencing (WES) and bioinformatics strategies to identify the pathogenic gene for this autosomal-dominant cardiac conduction disease (CCD) in a multi-generation pedigree. We examined four members of this family, including three affected and one unaffected. A novel nonsense mutation (Y1495X) in SCN5A was identified in the affected family members. This mutation is predicted to generate a truncated SCN5A protein, which could result in the loss of sodium current, a defined mechanism of SCN5A related arrhythmias. Our study provides evidence that WES is a highly effective approach for genetic analyses of rare clinical phenotypes. Our study also offers accurate genetic testing information for those yet clinically negative relatives.