Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%–11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pretest counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research—mechanistic, translational, and clinical—is urgently needed.

中文翻译：

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早发性房颤的基因检测


最近的大规模遗传学研究强调，心房颤动（AF）是一种全球流行的心律失常，具有重要的遗传基础。房颤、遗传性室性心肌病和心律失常综合征之间存在显着的临床和遗传重叠，强调了房颤作为年轻个体严重心室疾病早期指标的潜力。事实上，最近的几项研究已经证明，早发性房颤患者中罕见致病性变异的产量有意义（~4%–11%），尤其是心肌病基因，其中罕见变异被认为具有临床可操作性。因此，基因检测为识别与 AF 和遗传性心脏病（例如心肌病）相关的单基因缺陷提供了一个有希望的机会，并可能有助于早发 AF 患者的预后和治疗。 2023 年美国心脏病学会/美国心脏协会 AF 指南提出了对 45 岁或以下 AF 患者进行基因检测的 IIb 级建议，这是认识到这种单基因贡献的第一步。通过识别已知导致遗传性心肌病和心律失常综合征的致病性遗传变异，可以开发个性化护理途径，包括更有针对性的筛查、级联测试以及潜在的基于基因型的预后和预防措施。然而，这只能通过所有利益相关者开发和支持的框架来确保。测试结果的模糊性（例如意义不确定的变异）仍然是一个重大挑战，多达 60% 的早发性 AF 患者可能携带此类变异。 患者教育（包括预测试咨询）、遗传团队培训、高置信度基因的选择以及仔细报告是缓解这种情况的策略。实施的进一步挑战包括财务障碍、保险问题、劳动力限制以及快速发展的领域对标准化定义的需求。此外，普遍的遗传证据主要依赖于欧洲血统人群，这强调了多样化研究群体和国际合作的必要性。接受这些挑战和基因检测的潜力可能会改善房颤护理。然而，迫切需要进一步的研究——机械的、转化的和临床的。