Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.
Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Int J Legal Med. 2021 Jul;135(4):1341-1349. doi: 10.1007/s00414-021-02580-5. Epub 2021 Apr 25.
Sudden unexplained death (SUD) takes up a considerable part in overall sudden death cases, especially in adolescents and young adults. During the past decade, many channelopathy- and cardiomyopathy-associated single nucleotide variants (SNVs) have been identified in SUD studies by means of postmortem molecular autopsy, yet the number of cases that remain inconclusive is still high. Recent studies had suggested that structural variants (SVs) might play an important role in SUD, but there is no consensus on the impact of SVs on inherited cardiac diseases. In this study, we searched for potentially pathogenic SVs in 244 genes associated with cardiac diseases. Whole-exome sequencing and appropriate data analysis were performed in 45 SUD cases. Re-analysis of the exome data according to the current ACMG guidelines identified 14 pathogenic or likely pathogenic variants in 10 (22.2%) out of the 45 SUD cases, whereof 2 (4.4%) individuals had variants with likely functional effects in the channelopathy-associated genes SCN5A and TRDN and 1 (2.2%) individual in the cardiomyopathy-associated gene DTNA. In addition, 18 structural variants (SVs) were identified in 15 out of the 45 individuals. Two SVs with likely functional impairment were found in the coding regions of PDSS2 and TRPM4 in 2 SUD cases (4.4%). Both were identified as heterozygous deletions, which were confirmed by multiplex ligation-dependent probe amplification. In conclusion, our findings support that SVs could contribute to the pathology of the sudden death event in some of the cases and therefore should be investigated on a routine basis in suspected SUD cases.
不明原因的猝死 (SUD) 在所有猝死病例中占有相当大的比例，尤其是在青少年和年轻成年人中。在过去的十年中，通过死后分子尸检，在 SUD 研究中已经发现了许多与通道病和心肌病相关的单核苷酸变异 (SNV)，但仍有大量病例无法得出明确结论。最近的研究表明，结构变异 (SV) 可能在 SUD 中起重要作用，但 SV 对遗传性心脏病的影响尚无共识。在这项研究中，我们在 244 个与心脏病相关的基因中寻找可能的致病性 SV。对 45 例 SUD 病例进行了全外显子组测序和适当的数据分析。根据当前的 ACMG 指南对外显子组数据进行重新分析，在 45 例 SUD 病例中的 10 例 (22.2%) 中发现了 14 种致病性或可能致病性的变异，其中 2 例 (4.4%) 个体的通道病相关基因 SCN5A 和 TRDN 中的变异具有可能的功能影响，1 例 (2.2%) 个体的心肌病相关基因 DTNA 中的变异具有可能的功能影响。此外，在 45 名个体中的 15 名个体中发现了 18 种结构性变异 (SV)。在 2 例 SUD 病例中，在 PDSS2 和 TRPM4 的编码区发现了 2 种具有可能功能损害的 SV (4.4%)。这两种都是杂合性缺失，通过多重连接依赖性探针扩增得到证实。总之，我们的研究结果表明，SV 可能导致部分病例的猝死事件的病理变化，因此在疑似 SUD 病例中应常规进行调查。
