Importance Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined.

Objective To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes.

Design, Setting, and Participants This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021.

Main Outcomes and Measures The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD.

Results The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants.

Conclusions and Relevance In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

重要性 不明原因的心源性猝死 (SCD) 描述了未确定原因的 SCD。基因检测有助于诊断不明原因的 SCD 中的遗传性心脏病；然而，从未系统地检查过遗传性心肌病 (CM) 和心律失常综合征的致病性或可能致病性 (P/LP) 变异与生活在美国的白人和非裔美国成年人发生无法解释的 SCD 风险之间的关联。

目的 调查不明原因的 SCD 病例以确定遗传性 CM 和心律失常综合征的 P/LP 基因变异的频率。

设计、环境和参与者 这项遗传关联研究包括 683 名死于不明原因 SCD 的非裔美国人和白人成年人，并被纳入尸检登记处。总体而言，413 人的 DNA 质量可用于基因测序。数据收集时间为 1995 年 1 月至 2015 年 12 月。共对 30 个 CM 基因和 38 个心律失常基因进行了测序，并检查了这些基因中的变异体，以 P/LP 形式进行研究，以研究它们的频率。数据分析时间为 2018 年 6 月至 2021 年 3 月。

主要结果和测量 无法解释的 SCD 个体中 CM 或心律失常的 P/LP 变异频率。

结果 413 人的死亡年龄中位数（四分位距）为 41（29-48）岁，259 人（62.7%）为男性，208 人（50.4%）为非裔美国成年人。共有 76 名患有不明原因 SCD 的患者 (18.4%) 携带变异体，这些变异体被认为是 CM 和心律失常基因的 P/LP。总共有 52 名患者 (12.6%) 有 49 个 CM 的 P/LP 变异，22 名 (5.3%) 有 23 个心律失常的 P/LP 变异，2 名 (0.5%) 有 CM 和心律失常的 P/LP 变异。总体而言，在 45 名患者（10.9%）中发现了 41 个肥厚性 CM 的 P/LP 变异，在 11 名患者（2.7%）中发现了 9 个针对扩张型 CM 的 P/LP 变异，并且发现了 10 个针对长 QT 综合征的 P/LP 变异11 名患者（2.7%）。在有或没有 P/LP 变异的个体之间，临床和心脏特征没有显着差异。

结论和相关性 在这项对社区不明原因 SCD 病例的大型遗传关联研究中，近 20% 的患者携带 P/LP 变异，这表明遗传可能导致大量不明原因 SCD 病例。我们关于无法解释的 SCD 与 CM 基因和种族特异性遗传变异的关联的研究结果为这个知之甚少的实体提供了新的研究途径。