Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome.
Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome.
复制标题
DOI：
10.1016/j.jacc.2017.02.046
复制
发表时间：
2017-05-02
影响因子：
24
通讯作者：
Behr ER
中科院分区：
文献类型：
--
作者：
Lahrouchi N;Raju H;Lodder EM;Papatheodorou E;Ware JS;Papadakis M;Tadros R;Cole D;Skinner JR;Crawford J;Love DR;Pua CJ;Soh BY;Bhalshankar JD;Govind R;Tfelt-Hansen J;Winkel BG;van der Werf C;Wijeyeratne YD;Mellor G;Till J;Cohen MC;Tome-Esteban M;Sharma S;Wilde AAM;Cook SA;Bezzina CR;Sheppard MN;Behr ER
猝死综合征（SADS）描述了一种尸检和毒理学分析阴性的猝死。心脏遗传病可能是病因。本研究调查了SADS病例中尸检基因检测（分子尸检）的临床实用性和合并产率，并对幸存亲属进行了综合临床评估。我们评估了302例具有合适DNA的专业验证的SADS病例（中位年龄：24岁; 65%为男性），这些病例使用77个原发性电紊乱和心肌病基因的扩展组进行了下一代测序。使用美国医学遗传学学会（ACMG）共识指南对致病性和可能致病性变体进行分类。对82个存活的家系进行了分子尸检和临床评估相结合的产率评估。在SADS病例与对照组中进行基因水平的罕见变异关联分析。在302例病例中的40例（13%）中确定了临床上可采取行动的致病性或可能的致病性变体。确定的主要病因是儿茶酚胺能多形性室性心动过速和长QT综合征（分别为17例[6%]和11例[4%]）。基于基因的罕见变异关联分析显示RYR 2中罕见的预测有害变异富集（p = 5 × 10-5）。结合分子尸检和存活家庭的临床评估，诊断率从26%提高到39%。使用ACMG变异分类指南，对电紊乱和心肌病基因进行分子尸检，发现SADS的产量适中但现实。我们的数据强调了儿茶酚胺能多态性室性心动过速和长QT综合征的主要作用，特别是RYR 2基因，以及其他基因的最小产量。此外，我们显示了临床和遗传评估相结合的增强效用。
Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%. Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.