利用电子健康记录与遗传学的整合来研究单基因心律失常的患病率和表型负担。
Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics.
机构信息
Division of Cardiology, Department of Medicine (N.A.N., A.C.C., W.E.K., J.P.P., J.P.D., A.Y.S., S.H.S.), Durham, NC.
Department of Medicine (J.W.A.), Durham, NC.
出版信息
Circ Genom Precis Med. 2022 Oct;15(5):e003675. doi: 10.1161/CIRCGEN.121.003675. Epub 2022 Sep 22.
BACKGROUND
Inherited primary arrhythmia syndromes and arrhythmogenic cardiomyopathies can lead to sudden cardiac arrest in otherwise healthy individuals. The burden and expression of these diseases in a real-world, well-phenotyped cardiovascular population is not well understood.
METHODS
Whole exome sequencing was performed on 8574 individuals from the CATHGEN cohort (Catheterization Genetics). Variants in 55 arrhythmia-related genes (associated with 8 disorders) were identified and assessed for pathogenicity based on American College of Genetics and Genomics/Association for Molecular Pathology criteria. Individuals carrying pathogenic/likely pathogenic (P/LP) variants were grouped by arrhythmogenic disorder and matched 1:5 to noncarrier controls based on age, sex, and genetic ancestry. Long-term phenotypic data were annotated through deep electronic health record review.
RESULTS
Fifty-eight P/LP variants were found in 79 individuals in 12 genes associated with 5 arrhythmogenic disorders (arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, hypertrophic cardiomyopathy, -related cardiomyopathy, and long QT syndrome). The penetrance of these P/LP variants in this cardiovascular cohort was 33%, 0%, 28%, 83%, and 4%, respectively. Carriers of P/LP variants associated with arrhythmogenic disorders showed significant differences in ECG, imaging, and clinical phenotypes compared with noncarriers, but displayed no difference in survival. Carriers of novel truncating variants in , and also developed relevant arrhythmogenic cardiomyopathy phenotypes.
CONCLUSIONS
In a real-world cardiovascular cohort, P/LP variants in arrhythmia-related genes were relatively common (1:108 prevalence) and most penetrant in . While hypertrophic cardiomyopathy P/LP variant carriers showed significant differences in clinical outcomes compared with noncarriers, carriers of P/LP variants associated with other arrhythmogenic disorders displayed only ECG differences.
背景
遗传性原发性心律失常综合征和致心律失常性心肌病可导致原本健康的个体发生心源性猝死。这些疾病在现实世界中、表型良好的心血管人群中的负担和表现尚不清楚。
方法
对来自 CATHGEN 队列（导管遗传学）的 8574 名个体进行全外显子组测序。根据美国遗传与基因组学学院/分子病理学协会的标准，识别 55 个与心律失常相关的基因（与 8 种疾病相关）中的变异，并评估其致病性。根据年龄、性别和遗传背景，将携带致病性/可能致病性（P/LP）变异的个体按心律失常疾病分组，并与非携带者 1:5 匹配。通过深入的电子健康记录审查对长期表型数据进行注释。
结果
在 12 个与 5 种致心律失常疾病（致心律失常性右心室心肌病、Brugada 综合征、肥厚型心肌病、扩张型心肌病和长 QT 综合征）相关的基因中，发现了 79 名个体的 58 个 P/LP 变异。这些 P/LP 变异在心血管队列中的外显率分别为 33%、0%、28%、83%和 4%。与非携带者相比，携带与致心律失常疾病相关的 P/LP 变异的个体在心电图、影像学和临床表型方面存在显著差异，但生存率无差异。携带 、 和 新型截断变异的个体也出现了相关的致心律失常性心肌病表型。
结论
在现实世界的心血管队列中，心律失常相关基因中的 P/LP 变异相对常见（患病率为 1:108），在 中最具外显率。与非携带者相比，肥厚型心肌病 P/LP 变异携带者的临床结局存在显著差异，而携带其他致心律失常疾病相关 P/LP 变异的个体仅表现出心电图差异。
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