CVPath Institute, Gaithersburg, Maryland.
currently with Bioscience Cardiovascular Research and Early Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals Research and Development, AstraZeneca, Gaithersburg, Maryland.
JAMA Cardiol. 2021 Sep 1;6(9):1013-1022. doi: 10.1001/jamacardio.2021.1573.
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.
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.
The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD.
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.
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.
不明原因的心脏性猝死（SCD）描述的是没有确定病因的 SCD。基因检测有助于诊断不明原因 SCD 中的遗传性心脏病；然而，致病性或可能致病性（P/LP）变异与心律失常综合征以及白人和非裔美国人成年患者不明原因 SCD 风险之间的关联在美国从未被系统地研究过。
研究不明原因 SCD 的病例，以确定遗传性心肌病（CM）和心律失常综合征的 P/LP 基因突变的频率。
设计、地点和参与者：本项遗传关联研究纳入了 683 名因不明原因 SCD 死亡并纳入尸检登记处的非裔美国人和白人成年人。总体而言，有 413 名个体的 DNA 质量可接受测序。数据收集时间为 1995 年 1 月至 2015 年 12 月。对 30 个 CM 基因和 38 个心律失常基因进行了测序，并对这些基因中的变异进行了研究，将其分类为 P/LP，以研究其频率。数据分析于 2018 年 6 月至 2021 年 3 月进行。
不明原因 SCD 个体中 CM 或心律失常的 P/LP 变体的频率。
纳入的 413 名个体的中位（四分位间距）死亡年龄为 41（29-48）岁，259 名（62.7%）为男性，208 名（50.4%）为非裔美国人成年人。共有 76 名（18.4%）不明原因 SCD 患者携带 CM 和心律失常基因的 P/LP 变体。共有 52 名患者（12.6%）携带 49 个 P/LP 变异体用于 CM，22 名（5.3%）携带 23 个 P/LP 变异体用于心律失常，2 名（0.5%）携带 CM 和心律失常的 P/LP 变异体。共有 45 名患者（10.9%）发现 41 个肥厚性 CM 的 P/LP 变异体，11 名患者（2.7%）发现 9 个扩张性 CM 的 P/LP 变异体，11 名患者（2.7%）发现 10 个长 QT 综合征的 P/LP 变异体。在具有或不具有 P/LP 变异体的个体之间，临床和心脏特征没有显著差异。非裔美国人和白人患者同样可能携带 P/LP 变异体。
在这项针对社区不明原因 SCD 的大型遗传关联研究中，近 20%的患者携带 P/LP 变异体，这表明遗传因素可能导致相当数量的不明原因 SCD。我们关于不明原因 SCD 与 CM 基因和种族特异性遗传变异的关联的发现，为这一尚未完全了解的实体提供了新的研究途径。
