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

项目总结/摘要 大多数房颤（AF）病例是由临床风险因素和遗传易感性共同引起的。 此外，最近已经清楚，AF可能是罕见的高效应量变体的最早表现 与潜在致命的心脏通道病或心肌病（CM）相关。继承时 怀疑心律失常/CM综合征，目前的指南建议进行基因检测， 检测和降低心脏性猝死的风险。然而，目前的指南明确指出，遗传 通常不应对单独出现房颤的患者进行检测。因此，主要的知识差距是 如何识别AF是他们具有潜在严重潜在疾病的第一个迹象的患者， 遗传性疾病以及这些罕见遗传变异的心脏表型和临床意义。 我们现在可以使用NHLBI的精准医学跨组学来解决这些问题 （TOPMed）和NHGRI的常见疾病基因组学中心（CCDG）资源。TOPMed已执行 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2，852名早发性AF参与者 (age<60岁，遗传因素可能发挥特别重要作用的群体）来自范德比尔特 （范德比尔特TOPM房颤队列= 1，161，范德比尔特CCDG房颤队列= 1，691）。这些参与者被招募 来自范德比尔特房颤登记中心，并同意可能再次接触。为了创造一个更多样化的群体， 将从Meharry Medical前瞻性招募另外200名患有早发性AF的非裔美国人 学院利用这些资源，Aim 1将进行深入的表型分析，以确定AF的心脏表型 患有与遗传性心肌病相关的致病性或可能致病性（P/LP）罕见变异的患者 (CM)综合征（如致心律失常性CM、肥厚性CM、扩张性CM; Aim 1A）或遗传性心律失常 综合征（例如Brugada综合征、长QT综合征; Aim 1B）的患者中，并与对照组进行比较。的与会者 这些确定的遗传亚组和对照将被招募进行门诊研究访问， 心脏MRI、静息/应激/信号平均ECG和心脏监测。如果遗传性心律失常/CM综合征 如果被诊断出，将建议根据指南对医疗护理进行调整。目标2将创建预测 使用临床风险因素± AF多基因风险评分来识别P/LP罕见的AF患者的工具 基因变异，因此应该进行基因检测。 虽然测序技术的进步提高了人们对罕见和常见 遗传变异是房颤易感性的重要因素，房颤遗传亚群的表型尚不完整 定义了如果房颤的基因检测是为了增加治疗价值，我们的工作，以确定谁应该进行测试，并定义 需要在广泛的房颤人群中研究这些结果的临床意义。

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.