Kean Adam C, Helm Benjamin M, Vatta Matteo, Ayers Mark D, Parent John J, Darragh Robert K
Department of Pediatrics, Division of Pediatric Cardiology, Pediatric Electrophysiology, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Cardiol Young. 2019 Oct;29(10):1257-1263. doi: 10.1017/S1047951119001860.
The SCN5A gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel SCN5A variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest.
A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing.
All relatives tested were shown to have the same SCN5A variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring NEXN (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the SCN5A variant with an additional possible role for the NEXN variant in combination.
There is compelling clinical evidence suggesting that the SCN5A variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.
SCN5A基因与许多致心律失常和心肌病过程有关。我们在一个家族中发现了一种新的SCN5A变异体，该家族中患有进行性窦房结和房室结疾病、房性心律失常、扩张型心肌病以及早期心脏性猝死的个体中存在明显的分离现象。
在对三名受影响个体（一对同卵双胞胎和一个同父异母的兄弟）进行临床评估后绘制了患者家系图，这导致对一个同父异母的姐妹（四个同父但母亲不同的兄弟姐妹）进行评估，他们除了有一位父亲在50多岁时不明原因死亡且尸检结果相似的家族史外，均经历了不同程度的房性心律失常、传导疾病和扩张型心肌病。索引男性对58个与心肌病相关的基因进行了测序。桑格测序用于为覆盖不足的碱基以及基因组片段重复的一些已知区域中的碱基提供数据。所有具有临床意义的新变异体均通过独立的桑格测序进行了确认。
所有检测的亲属均显示具有相同的意义不明的SCN5A变异体（p.Asp197His），同卵双胞胎还共同存在一个NEXN变异体（p.Glu575*）。分离分析表明SCN5A变异体可能具有致病特性，NEXN变异体可能具有额外的联合作用。
有令人信服的临床证据表明，基于我们感兴趣的家族的分离分析，SCN5A变异体p.Asp197His可能被重新分类为可能致病。分子机制研究有待进行。
