Probing Phenotype-Genotype Relations After Whole Genome Sequencing in Patients with Atrial Fibrillation

项目摘要/摘要 大多数房颤(AF)病例是由临床危险因素和遗传易感性共同作用的结果。 此外，最近明确的是，房颤可能是罕见的高效果大小变异的最早表现 与潜在的致命性心脏通道病或心肌病(CM)相关。当继承时 怀疑心律失常/CM综合征，当前指南建议进行基因检测以实现早期 检测并降低心源性猝死的风险。然而，目前的指导方针明确指出，基因 通常不应该在单独出现房颤的患者中进行测试。因此，主要的知识差距是 如何识别房颤是其具有潜在严重潜在危险的首个征兆 遗传性疾病以及这些罕见的基因变异的心脏表型和临床意义。 我们现在能够使用NHLBI的精密医学反式组学来解决这些问题 (TOPMed)和NHGRI的常见病基因组学中心(CCDG)资源。TOPMed已经完成了 全基因组测序(WGS)和CCDG已经进行了大量的全外显子组测序(WES 患有常见心血管疾病的受试者。目前，这包括2852名早发性房颤患者 (60岁，遗传因素可能在其中发挥特别重要作用的群体) (Vanderbilt TOPMed AF Cohort=1,161，Vanderbilt CCDG AF Cohort=1,691)这些参与者是招募的 来自范德比尔特AF注册处，并已同意可能的重新联系。为了创造一个更多样化的群体，一个 预计将从Meharry Medical招募另外200名患有早发性房颤的非裔美国人 上大学。利用这些资源，Aim 1将进行深入的表型分析，以确定房颤的心脏表型 与遗传性心肌病相关的致病或可能致病(P/LP)罕见变异的患者 (Cm)综合征(如致心律失常型心肌梗死、肥厚型心肌梗死、扩张心肌梗死；目标1A)或遗传性心律失常 (例如，Brugada综合征、长QT综合征；Aim 1B)，并与对照组进行比较。参与者来自 这些确定的基因亚群和对照将被招募用于门诊研究访问，以进行 心脏MRI、静息/负荷/平均信号的ECG和心脏监测。如果遗传性心律失常/CM综合征 一旦确诊，将建议对医疗保健进行指导方针的改变。目标2将创建一个预测 使用临床危险因素±房颤多基因风险评分来识别罕见P/LP的房颤患者的工具 基因变异，因此应接受基因检测。 虽然测序技术的进步提高了人们对稀有和常见 遗传变异导致房颤易感性，房颤遗传亚群的表型尚不完全 已定义。如果房颤的基因检测是为了增加治疗价值，我们的工作是确定哪些人应该接受检测并定义 这些结果在广泛的房颤人群中的临床意义是必要的。

PROJECT SUMMARY/ABSTRACT Most cases of atrial fibrillation (AF) arise from a combination of clinical risk factors and genetic susceptibility. Moreover, it has recently become clear that AF can be the earliest manifestation of rare high effect size variants associated with potentially fatal cardiac channelopathies or cardiomyopathies (CM). When inherited arrhythmia/CM syndromes are suspected, current guidelines recommend genetic testing to enable early detection and reduce the risk of sudden cardiac death. However, current guidelines specifically state that genetic testing should not ordinarily be performed in patients presenting with AF alone. Thus, major knowledge gaps are how to identify those patients in whom AF is the first sign that they possess a potentially serious underlying genetic disease and what is the cardiac phenotype and clinical significance of those rare genetic variants. We are now in a position to address these issues using the NHLBI’s Trans-omics for Precision Medicine (TOPMed) and NHGRI’s Centers for Common Disease Genomics (CCDG) resources. TOPMed has performed whole genome sequencing (WGS) and CCDG has performed whole exome sequencing (WES) in large numbers of subjects with common cardiovascular diseases. Currently, this includes 2,852 participants with early onset AF (age <60 years, a group in which genetic factors may play an especially important role) from Vanderbilt (Vanderbilt TOPMed AF Cohort=1,161, Vanderbilt CCDG AF Cohort=1,691). These participants were recruited from Vanderbilt AF registries and have consented for potential recontact. To create a more diverse cohort, an additional 200 African Americans with early onset AF will be prospectively recruited from Meharry Medical College. Using these resources, Aim 1 will perform deep phenotyping to define the cardiac phenotype of AF patients with a pathogenic or likely pathogenic (P/LP) rare variant associated with an inherited cardiomyopathy (CM) syndrome (e.g. arrhythmogenic CM, hypertrophic CM, dilated CM; Aim 1A) or inherited arrhythmia syndrome (e.g. Brugada Syndrome, Long QT Syndrome; Aim 1B) and compared to controls. Participants from these defined genetic subgroups and controls will be recruited for an outpatient research visit to undergo a cardiac MRI, rest/stress/signal-averaged ECGs, and cardiac monitoring. If an inherited arrhythmia/CM syndrome is diagnosed, guideline-directed changes to medical care will be recommended. Aim 2 will create a prediction tool using clinical risk factors ± an AF polygenic risk score to identify patients with AF who have a P/LP rare genetic variant and therefore should undergo genetic testing. While advances in sequencing technology have improved the understanding of how rare and common genetic variation contributes to AF susceptibility, the phenotype of AF genetic subgroups remains incompletely defined. If genetic testing for AF is to add therapeutic value, our work to identify who should be tested and define the clinical implications of these results in a broad AF population is needed.