Post-mortem Whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series.
Post-mortem Whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series.
复制标题
验尸整个外显子组测序与基因特异性分析，用于年轻人的尸检突然无法解释的死亡：病例系列。
DOI：
10.1007/s00246-014-1082-4
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发表时间：
2015-04
影响因子：
1.6
通讯作者：
Ackerman MJ
中科院分区：
文献类型：
--
作者：
Narula N;Tester DJ;Paulmichl A;Maleszewski JJ;Ackerman MJ
每年，经过全面的法医尸检后，仍有数千名 35 岁以下的人突然死亡，但仍无法解释。此前，通过桑格测序对 4 个主要心脏通道病基因进行的尸检遗传分析显示，尸检阴性的青少年不明原因猝死 (SUDY) 病例中大约四分之一存在潜在突变。然而，现在有超过 100 个诱发猝死的心脏通道病、心肌病和代谢紊乱易感基因。在这里，我们着手确定死后全外显子组测序（WES）是否是检测超罕见、潜在致病变异的有效策略。我们对 14 名连续转诊的白人 SUDY 受害者（平均死亡年龄 17.4 ± 8.6 岁）的 117 个猝死易感基因进行了尸检 WES 和基因特异性分析，以确定假定的 SUDY 相关突变。平均而言，每个 SUDY 病例都有 12,758 ± 2016 个非同义变异，其中 79 ± 15 个定位于这 117 个基因。总体而言，在 14 例病例中的 7 例 (50%) 中，在 6 个基因（TTN 中 3 个，CACNA1C、JPH2、MYH7、VCL、RYR2 各 1 个）中发现了 3 个公开的外显子组数据库中不存在的 8 个极其罕见的变异（7 个错义，1 个框内插入）。在 7 个错义改变中，3 个独立的计算机工具预测了 2 个（T171M-CACNA1C、I22160T-TTN）的损害。尽管 WES 和基因特异性监测是检测可能构成死亡致病原因的罕见遗传变异的有效方法，但准确解释每种变异仍具有挑战性。必须保持高度克制和谨慎，避免过早且错误地告知家属根本原因已找到。
Annually, thousands of sudden deaths in individuals under 35 years remain unexplained following comprehensive medico-legal autopsy. Previously, post-mortem genetic analysis by Sanger-sequencing of 4 major cardiac channelopathy genes revealed that approximately one-fourth of these autopsy-negative sudden unexplained death in the young (SUDY) cases harbored an underlying mutation. However, there are now over 100 sudden death predisposing cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes. Here, we set out to determine whether post-mortem whole exome sequencing (WES) is an efficient strategy to detect ultra-rare, potentially pathogenic variants. We performed post-mortem WES and gene-specific analysis of 117 sudden death-susceptibility genes for 14 consecutively-referred Caucasian SUDY victims (average age at death 17.4 ± 8.6 years) to identify putative SUDY-associated mutations. On average, each SUDY case had 12,758 ± 2016 non-synonymous variants, of which 79 ± 15 localized to these 117 genes. Overall, 8 ultra-rare variants (7 missense, 1 in-frame insertion) absent in 3 publically available exome databases were identified in 6 genes (3 in TTN, and 1 each in CACNA1C, JPH2, MYH7, VCL, RYR2) in 7 of 14 cases (50%). Of the 7 missense alterations, 2 (T171M-CACNA1C, I22160T-TTN) were predicted damaging by 3 independent in-silico tools. Although WES and gene-specific surveillance is an efficient means to detect rare genetic variants that might underlie the pathogenic cause of death, accurate interpretation of each variant is challenging. Great restraint and caution must be exercised less families be informed prematurely and incorrectly that the root cause has been found.