Importance Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome.

Objective To examine the results of genetic testing for early-onset AF.

Design, Setting, and Participants This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021.

Exposures Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories.

Main Outcomes and Measures Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders.

Results Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8).

Conclusions and Relevance In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.

重要性 早发性心房颤动 (AF) 可能是更严重的潜在遗传性心肌病或心律失常综合征的最初表现。

目的 探讨早发性房颤基因检测结果。

设计、设置和参与者 这项前瞻性、观察性队列研究招募了来自学术医疗中心的参与者，他们在 66 岁之前被诊断为 AF，并通过国家心肺血液研究所的精准医学跨组学计划接受了全基因组测序. 参与者于 1999 年 11 月 23 日至 2015 年 6 月 2 日入组。数据分析于 2020 年 10 月 24 日至 2021 年 3 月 11 日进行。

在商业临床基因检测实验室使用的心肌病和心律失常面板中发现的 145 个基因组中发现了罕见变异。

主要结果和措施 使用自动化过程分析测序数据，然后由一组独立的盲审者进行手动审查。主要结果是使用美国医学遗传学和基因组学学院标准对罕见变异进行分类：良性、可能良性、意义未确定的变异、可能致病或致病。疾病相关变异被定义为与常染色体显性或 X 连锁显性疾病相关的基因中的致病/可能致病变异。

结果 在 1293 名参与者（934 [72.2%] 男性；入组时的中位 [四分位距] 年龄，56 [48-61] 岁；诊断 AF 时的中位 [四分位距] 年龄，50 [41-56] 岁）中，基因检测确定131 名参与者 (10.1%) 有疾病相关变异，812 名 (62.8%) 有未确定意义的变异，92 名 (7.1%) 是常染色体隐性遗传病的杂合子携带者，258 名 (20.0%) 没有可疑变异。疾病相关变异的可能性在 30 岁之前诊断为 AF 的参与者中最高（119 人中有 20 人 [16.8%；95% CI，10.0%-23.6%]），在 60 岁之后最低（8 112 [7.1%；95% CI，2.4%-11.9%]）。与遗传性心律失常相比，疾病相关变异更常与遗传性心肌病综合征相关。最常见的基因是TTN (n = 38)、MYH7 (n = 18)、MYH6 (n = 10)、LMNA (n = 9) 和KCNQ1 (n = 8)。

结论和相关性 在这项队列研究中，基因检测在 10% 的早发性 AF 患者中发现了疾病相关变异（如果在 30 岁之前诊断该百分比较高，如果在 60 岁之后诊断该百分比较低） . 大多数致病/可能的致病变异存在于与心肌病相关的基因中。这些结果支持在早发性 AF 中使用基因检测。