National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore.
Defence Medical and Environmental Research Institute, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore Saw Swee Hock School of Public Health, Tahir Foundation Building, National University of Singapore, 12 Science Drive 2, Singapore 117549, Singapore.
Europace. 2016 Jun;18(6):897-904. doi: 10.1093/europace/euv058. Epub 2015 Mar 31.
Brugada syndrome (BrS) is a rare heritable ventricular arrhythmia. Genetic defects in SCN5A, a gene that encodes the α-subunit of the sodium ion channel Nav1.5, are present in 15-30% of BrS cases. SCN5A remains by far, the highest yielding gene for BrS. We studied a young male who presented with syncope at age 11. This proband was screened for possible disease causing SCN5A mutations. The inheritance pattern was also examined amongst his first-degree family members.
The proband had a baseline electrocardiogram that showed Type 2 BrS changes, which escalated to a characteristic Type I BrS pattern during a treadmill test before polymorphic ventricular tachycardia onset at a cycle length of 250 ms. Mutational analysis across all 29 exons in SCN5A of the proband and first-degree relatives of the family revealed that the proband inherited a compound heterozygote mutation in SCN5A, specifically p.A226V and p.R1629X from each parent. To further elucidate the functional changes arising through these mutations, patch-clamp electrophysiology was performed in TSA201 cells expressing the mutated SCN5A channels. The p.A226V mutation significantly reduced peak sodium current (INa) to 24% of wild type (WT) whereas the p.R1629X mutation abolished the current. To mimic the functional state in our proband, functional expression of the compound variants A226V + R1629X resulted in overall peak INa of only 13% of WT (P < 0.01).
Our study is the first to report a SCN5A compound heterozygote in a Singaporean Chinese family. Only the proband carrying both mutations displayed the BrS phenotype, thus providing insights into the expression and penetrance of BrS in an Asian setting.
Brugada 综合征（BrS）是一种罕见的遗传性室性心律失常。编码钠离子通道 Nav1.5α亚单位的 SCN5A 基因的遗传缺陷存在于 15-30%的 BrS 病例中。到目前为止，SCN5A 仍然是 BrS 最高产的基因。我们研究了一位 11 岁时出现晕厥的年轻男性。该先证者接受了可能导致 SCN5A 突变的疾病筛查。还检查了他一级亲属中的遗传模式。
先证者的基线心电图显示 2 型 BrS 改变，在跑步机测试期间升级为特征性 1 型 BrS 模式，随后在 250 ms 心动周期时出现多形性室性心动过速。对先证者和家族一级亲属的 SCN5A 所有 29 个外显子进行突变分析，发现先证者从父母双方遗传了 SCN5A 的复合杂合突变，具体为 p.A226V 和 p.R1629X。为了进一步阐明这些突变引起的功能变化，在表达突变 SCN5A 通道的 TSA201 细胞中进行了膜片钳电生理学研究。p.A226V 突变使峰值钠电流（INa）显著减少至野生型（WT）的 24%，而 p.R1629X 突变则使电流消失。为了模拟我们先证者的功能状态，复合变体 A226V + R1629X 的功能表达导致 INa 的总峰值仅为 WT 的 13%（P < 0.01）。
我们的研究首次报道了新加坡华裔家族中的 SCN5A 复合杂合突变。只有携带两种突变的先证者表现出 BrS 表型，从而为亚洲人群中的 BrS 表达和外显率提供了见解。
