Supplementary Material for: A Novel <b><i>SCN5A</i></b> Variant Associated with Abnormal Repolarization, Atrial Fibrillation, and Reversible Cardiomyopathy

A variety of life-threating arrhythmias are caused by mutations in the cardiac voltage-gated sodium channel encoded by the<i> SCN5A</i> gene. In this study, we report a novel loss-of-function <i>SCN5A</i> variant, p.Ile1343Val (c.4027A&gt;G), identified in a 42-year-old proband who presented with an unusual ECG with abnormal repolarization with biphasic T-waves in anteroseptal leads, persistent atrial fibrillation (AF), intermittent left bundle branch block (LBBB), and reversible cardiomyopathy. The patient did not meet the diagnostic criteria for Brugada syndrome, long QT syndrome, or any other known <i>SCN5A</i>-associated phenotype. Characterization of the biophysical properties of the variant by in vitro<i></i> patch clamp experiments revealed a reduced Na⁺ current with no effect on the inactivation kinetics of the channel. This loss-of-function of Na⁺ current could explain the intermittent LBBB as well as the AF. In conclusion, we describe a unique combination of electrical and structural abnormalities associated with a novel <i>SCN5A</i> variant. Our findings broaden the spectrum of cardiac phenotypes associated with <i>SCN5A</i> channelopathy, underlining the complex clinical manifestations of genetic variations within this gene.多种致命性心律失常由<i>SCN5A</i>基因编码的心脏电压门控钠通道突变引发。本研究报道了一例新型功能丧失型<i>SCN5A</i>变异体p.Ile1343Val（c.4027A>G），该变异体检出自一名42岁先证者，该患者表现出异常心电图特征：前间隔导联出现双相T波伴复极异常，合并持续性心房颤动（atrial fibrillation, AF）、间歇性左束支传导阻滞（left bundle branch block, LBBB）以及可逆性心肌病。该患者不符合布鲁加达综合征、长QT综合征或其他任何已知的<i>SCN5A</i>相关表型的诊断标准。通过体外膜片钳实验对该变异体的生物物理特性进行表征，结果显示其钠电流降低，但对通道的失活动力学无影响。这种钠电流的功能丧失性可解释间歇性左束支传导阻滞与心房颤动的发生。综上，我们描述了一种与新型<i>SCN5A</i>变异体相关的独特电学与结构异常组合。本研究结果拓宽了<i>SCN5A</i>通道病相关的心脏表型谱，凸显了该基因内遗传变异的复杂临床表现。

搜集汇总

背景与挑战

背景概述

该数据集是2018年发布的补充材料，聚焦于一项医学研究，报告了一种新的SCN5A基因功能丧失变异（p.Ile1343Val），该变异与异常复极、心房颤动和可逆性心肌病相关。研究通过体外实验揭示了变异导致钠电流减少的机制，并扩展了SCN5A通道病的表型谱，强调了基因变异的复杂临床表现。