Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (G.W.S., D.J.T., J.P.A., M.J.A.).
King's College London, United Kingdom (M.A.S.).
Circulation. 2018 Jun 19;137(25):2705-2715. doi: 10.1161/CIRCULATIONAHA.117.031053.
Potentially lethal cardiac channelopathies/cardiomyopathies may underlie a substantial portion of sudden unexplained death in the young (SUDY). The whole-exome molecular autopsy represents the latest approach to postmortem genetic testing for SUDY. However, proper variant adjudication in the setting of SUDY can be challenging.
From January 2012 through December 2013, 25 consecutive cases of SUDY from 1 to 40 years of age (average age at death 27±5.7 years; 13 white, 12 black) from Cook County, Illinois, were referred after a negative (n=16) or equivocal (n=9) conventional autopsy. A whole-exome molecular autopsy with analysis of 99 sudden death-susceptibility genes was performed. The predicted pathogenicity of ultrarare, nonsynonymous variants was determined using the American College of Medical Genetics guidelines.
Overall, 27 ultrarare nonsynonymous variants were seen in 16/25 (64%) victims of SUDY. Among black individuals, 9/12 (75%) had an ultrarare nonsynonymous variant compared with 7/13 (54%) white individuals. Of the 27 variants, 10 were considered pathogenic or likely pathogenic in 7/25 (28%) individuals in accordance with the American College of Medical Genetics guidelines. Pathogenic/likely pathogenic variants were identified in 5/16 (31%) of autopsy-negative cases and in 2/6 (33%) victims of SUDY with equivocal findings of cardiomyopathy. Overall, 6 pathogenic/likely pathogenic variants in 4/25 (16%) cases were congruent with the phenotypic findings at autopsy and therefore considered clinically actionable.
Whole-exome molecular autopsy with gene-specific surveillance is an effective approach for the detection of potential pathogenic variants in SUDY cases. However, systematic variant adjudication is crucial to ensure accurate and proper care for surviving family members.
潜在致命性的心脏通道病/心肌病可能是年轻人不明原因猝死（SUDY）的主要原因。全外显子组分子尸检代表了 SUDY 死后基因检测的最新方法。然而，在 SUDY 的背景下进行适当的变异裁决可能具有挑战性。
从 2012 年 1 月至 2013 年 12 月，伊利诺伊州库克县连续 25 例年龄在 1 至 40 岁之间的 SUDY（平均死亡年龄 27±5.7 岁；13 名白人，12 名黑人）在常规尸检阴性（n=16）或不确定（n=9）后被转介。进行了全外显子组分子尸检，分析了 99 个易发生猝死的基因。使用美国医学遗传学学院的指南确定超罕见、非同义变异的预测致病性。
总体而言，25 例 SUDY 患者中有 16 例（64%）发现 27 个超罕见非同义变异。在黑人个体中，12 例中有 9 例（75%）发现超罕见非同义变异，而白人个体中为 13 例中有 7 例（54%）。在 27 个变异中，根据美国医学遗传学学院的指南，有 10 个被认为具有致病性或可能致病性，在 25 名患者中有 7 名（28%）符合该标准。在尸检阴性的 16 例病例中，有 5 例（31%）和 SUDY 中发现心肌病变的 6 例不确定结果中，有 2 例（33%）发现了致病性/可能致病性变异。总体而言，在 25 例病例中有 4 例（16%）发现了 6 个致病性/可能致病性变异，与尸检的表型发现一致，因此被认为具有临床可操作性。
全外显子组分子尸检与基因特异性监测相结合是检测 SUDY 病例中潜在致病变异的有效方法。然而，系统的变异裁决对于确保准确和适当的护理幸存者家属至关重要。
