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首页> 外文期刊>Circulation journal >Contribution of Cardiac Sodium Channel β-Subunit Variants to Brugada Syndrome
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Contribution of Cardiac Sodium Channel β-Subunit Variants to Brugada Syndrome

机译：心脏钠通道β亚基变异体对Brugada综合征的贡献

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Background: Brugada syndrome (BrS) is an inheritable cardiac disease associated with syncope, malignant ventricular arrhythmias and sudden cardiac death. The largest proportion of mutations in BrS is found in the SCN5A gene encoding the α-subunit of cardiac sodium channels (Nav1.5). Causal SCN5A mutations are present in 18–30% of BrS patients. The additional genetic diagnostic yield of variants in cardiac sodium channel β-subunits in BrS patients was explored and functional studies on 3 novel candidate variants were performed. Methods?and?Results: The SCN1B - SCN4B genes were screened, which encode the 5 sodium channel β-subunits, in a SCN5A negative BrS population (n=74). Five novel variants were detected; in silico pathogenicity prediction classified 4 variants as possibly disease causing. Three variants were selected for functional study. These variants caused only limited alterations of Nav1.5 function. Next generation sequencing of a panel of 88 arrhythmia genes could not identify other major causal mutations. Conclusions: It was hypothesized that the studied variants are not the primary cause of BrS in these patients. However, because small functional effects of these β-subunit variants can be discriminated, they might contribute to the BrS phenotype and be considered a risk factor. The existence of these risk factors can give an explanation to the reduced penetrance and variable expressivity seen in this syndrome. We therefore recommend including the SCN1-4B genes in a next generation sequencing-based gene panel. ( Circ J 2015; 79: 2118–2129)
机译：背景：Brugada综合征（BrS）是一种与晕厥，恶性室性心律不齐和心源性猝死相关的遗传性心脏病。 BrS中最大比例的突变出现在编码心脏钠通道α-亚基的SCN5A基因中（Nav1.5）。 18–30％的BrS患者中存在因果SCN5A突变。探索了BrS患者心脏钠通道β亚基变异体的额外遗传诊断率，并进行了3种新的候选变异体的功能研究。方法和结果：在SCN5A阴性BrS群体（n = 74）中筛选出编码5个钠通道β亚基的SCN1B-SCN4B基因。检测到五个新颖的变体。在计算机病原学预测中，将4个变异体归类为可能的致病原因。选择了三个变体进行功能研究。这些变体仅引起Nav1.5功能的有限更改。一组88个心律失常基因的下一代测序无法确定其他主要的因果突变。结论：假设研究的变异不是这些患者BrS的主要原因。但是，由于可以区分这些β亚基变体的小功能作用，因此它们可能有助于BrS表型，并被认为是危险因素。这些危险因素的存在可以解释这种综合征中外显率的降低和表现力的变化。因此，我们建议将SCN1-4B基因包括在下一代基于测序的基因组中。 （Circ J 2015; 79：2118-2129）

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