Neves Raquel, Tester David J, Simpson Michael A, Behr Elijah R, Ackerman Michael J, Giudicessi John R
Division of Heart Rhythm Services, Departments of Cardiovascular Medicine (R.N., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN.
Division of Pediatric Cardiology, Pediatric and Adolescent Medicine (R.N., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN.
Circ Genom Precis Med. 2022 Feb;15(1):e003497. doi: 10.1161/CIRCGEN.121.003497. Epub 2021 Dec 24.
Sudden cardiac arrest (SCA) and sudden unexplained death (SUD) are feared sequelae of many genetic heart diseases. In rare circumstances, pathogenic variants in cardiomyopathy-susceptibility genes may result in electrical instability leading to SCA/SUD before any structural manifestations of underlying cardiomyopathy are evident.
Collectively, 38 unexplained SCA survivors (21 males; mean age at SCA 26.4±13.1 years), 68 autopsy-inconclusive SUD cases (46 males; mean age at death 20.4±9.0 years) without disease-causative variants in the channelopathy genes, and 973 ostensibly healthy controls were included. Following exome sequencing, ultrarare (minor allele frequency ≤0.00005 in any ethnic group within Genome Aggregation Database [gnomAD, N=141 456 individuals]) nonsynonymous variants identified in 24 Clinical Genome Resource adjudicated definitive/strong evidence cardiomyopathy-susceptibility genes were analyzed. Eligible variants were adjudicated as pathogenic, likely pathogenic, or variant of uncertain significance in accordance with current American College of Medical Genetics and Genomics guidelines.
Overall, 7 out of 38 (18.4%) SCA survivors and 14 out of 68 (20.5%) autopsy-inconclusive, channelopathic-negative SUD cases had at least one pathogenic/likely pathogenic or a variant of uncertain significance nonsynonymous variant within a strong evidence, cardiomyopathy-susceptibility gene. Following American College of Medical Genetics and Genomics criterion variant adjudication, a pathogenic or likely pathogenic variant was identified in 3 out of 38 (7.9%; =0.05) SCA survivors and 8 out of 68 (11.8%; =0.0002) autopsy-inconclusive SUD cases compared to 20 out of 973 (2.1%) European controls. Interestingly, the yield of pathogenic/likely pathogenic variants was significantly greater in autopsy-inconclusive SUD cases with documented interstitial fibrosis (4/11, 36%) compared with only 4 out of 57 (7%, <0.02) SUD cases without ventricular fibrosis.
Our data further supports the inclusion of strong evidence cardiomyopathy-susceptibility genes on the genetic testing panels used to evaluate unexplained SCA survivors and autopsy-inconclusive/negative SUD decedents. However, to avoid diagnostic miscues, the careful interpretation of genetic test results in patients without overt phenotypes is vital.
心脏性猝死（SCA）和不明原因猝死（SUD）是许多遗传性心脏病令人担忧的后遗症。在罕见情况下，心肌病易感基因中的致病变异可能导致电不稳定，在潜在心肌病的任何结构表现明显之前就引发SCA/SUD。
总共纳入了38名不明原因SCA幸存者（21名男性；SCA时平均年龄26.4±13.1岁）、68例尸检无定论的SUD病例（46名男性；死亡时平均年龄20.4±9.0岁），这些病例在通道病基因中没有致病变体，以及973名表面健康的对照者。外显子组测序后，分析了在24个临床基因组资源判定为明确/有力证据的心肌病易感基因中鉴定出的超罕见（基因组聚合数据库[gnomAD，N = 141 456人]中任何种族的次要等位基因频率≤0.00005）非同义变体。根据当前美国医学遗传学与基因组学学会的指南，将符合条件的变体判定为致病、可能致病或意义未明的变体。
总体而言，38名SCA幸存者中有7名（18.4%），68例尸检无定论、通道病阴性的SUD病例中有14名（20.5%）在有力证据的心肌病易感基因内至少有一个致病/可能致病或意义未明的非同义变体。根据美国医学遗传学与基因组学学会的标准变体判定，在38名SCA幸存者中有3名（7.9%；P = 0.05）、68例尸检无定论的SUD病例中有8名（11.8%；P = 0.0002）鉴定出致病或可能致病的变体，而973名欧洲对照者中有20名（2.1%）。有趣地是，有间质纤维化记录的尸检无定论的SUD病例中致病/可能致病变体的检出率（4/11，36%）显著高于无间质纤维化的57例SUD病例中仅4例（7%，P < 0.02）。
我们的数据进一步支持在用于评估不明原因SCA幸存者和尸检无定论/阴性SUD死者的基因检测面板中纳入有力证据的心肌病易感基因。然而，为避免诊断错误，对无明显表型患者的基因检测结果进行仔细解读至关重要。
