Investigating structural and genetic substrates of early-onset atrial fibrillation

项目摘要/摘要 早发性心房颤动(35岁前首次发生的房颤)与频繁发作有关 复发，通常需要电击来停止心律失常，药物预防心律失常或 外科/介入治疗。最近的研究表明，成人对房颤的干预 (房颤)不能有效改变儿童和年轻人的复发频率。在临床实践中， 儿科心脏病专家不遵循为成人设计的房颤建议。关于治疗的建议 尚未在早发性房颤中得到证实，部分原因是我们目前可能评估了错误的标记物 为了冒险。我们的中心假设是可识别的遗传因素与临床复发有关 ≤中35岁的儿童和青年房颤患者。我们将使用三种基因组方法来解决 我们的中心假设：一个有效的基因小组(目标1)，共同变异分析(目标2A)，以及罕见的变异 全基因组测序分析(目标2B)。我们将在多中心招募早发性房颤患者 网络。在一项前瞻性的观察性研究中，我们将记录表型信息并获得遗传物质。 在我们的第一个目标中，我们将确定311中具有致病和可能致病(P/LP)变异的患者 已确定的心脏基因与无P/LP变异的患者相比，首次房颤复发的时间更短。通过 在商业化的面板中测试与临床相关的基因，我们将能够快速转换结果 我们的第一个目标是临床实践。在第二个目标中，我们将关注新的基因组关系。数据来自 对老年人房颤的全基因组关联研究已经产生了多基因风险评分(PR)。高分 与老年人发病率和死亡率的增加有关。然而，目前尚不清楚 房颤反应是否与儿童和年轻人有关，或者是否是终生的标志 基因组和肌病风险。因此，我们将验证现有的房颤比率在早发性房颤中是否更高 在没有心脏表型的对照人群中。最后，在第二次基因组分析中，我们识别出 研究目标1中没有P/LP变异体的先证者。从那些P/LP阴性的先证者中，我们将识别 先证者有早发性房颤且父母双方均无心脏病且阴性的三人组 早发性房颤家族史。我们将进行三个全基因组测序，以确定新的遗传标记 早发性房颤的风险。如果我们的中心假设是正确的，这三种方法将确定一组新的 早发性房颤的危险因素。直接的影响将是测试商业上可获得的基因的能力 确定早期房颤复发风险和可能确定进展的终身风险的异常 肌病，对治疗和预防的影响。作为第二个好处，P/LP变种的识别 先证者对家庭中的级联筛查有影响。最后，在基因组的基础上工作 早发性房颤不仅在年轻人中有意义，而且作为一种假说，心房肌病的终生风险 影响老年人心房颤动的后期发病率。

PROJECT SUMMARY/ABSTRACT Early-onset atrial fibrillation (a first event of atrial fibrillation before 35 years of age) is associated with frequent recurrences, often requiring electrical shocks to stop the arrhythmia, medication to prevent arrhythmia or surgical/interventional management. Recent work has demonstrated that adult interventions for atrial fibrillation (AF) are not effective in changing the frequency of recurrence in children and young adults. In clinical practice, pediatric cardiologists do not follow the AF recommendations designed for adults. Recommendations for therapy have not been established in early-onset AF, in part because we may be currently assessing the wrong markers for risk. Our central hypothesis is that identifiable genetic factors are associated with clinical recurrence in children and young adults with AF at ≤ 35 years of age. We will use three genomic approaches to addressing our central hypothesis: a validated gene panel (Aim 1), common-variant analysis (Aim 2A), and rare variant analysis with whole genome sequencing (Aim 2B). We will recruit patients with early-onset AF in a multicenter network. In a prospective, observational study, we will record phenotype information and obtain genetic material. In our first aim, we will determine if patients with pathogenic and likely pathogenic (P/LP) variants in 311 established cardiac genes have a shorter time to first AF recurrence than patients without a P/LP variant. By testing clinically relevant genes in commercially available panels, we will be able to rapidly translate the results of our first aim to clinical practice. In the second aim, we will focus on new genomic relationships. Data from genome-wide association studies of AF in older adults have generated polygenic risk scores (PRS). High scores on PRS have been associated with increased morbidity and mortality in older adults. However, it is not known whether AF PRS have any relevance in children and young adults, nor whether they are markers of lifelong genomic and myopathic risk. Therefore, we will validate whether existing AF PRS are higher in early-onset AF than in a control population without cardiac phenotype. Finally, in a second genomic analysis, we identify probands who have no P/LP variants in Aim 1 of the study. From those P/LP-negative probands, we will identify trios where the proband has early-onset AF and both parents are negative for cardiac disease with a negative family history of early-onset AF. We will perform trio whole genome sequencing to identify novel genetic markers of risk in early-onset AF. If our central hypothesis is correct, these three approaches will identify a novel set of risk factors in early-onset AF. The immediate impact will be the ability to test for commercially available genetic abnormalities that identify risk of early AF recurrence and that may identify lifelong risk for progression of myopathy, with implications for therapy and prevention. As a secondary benefit, the identification of P/LP variants in a proband has implications for cascade screening in families. Finally, work on the genomic underpinnings of early-onset AF has implications not only in the young, but as a hypothesis that the lifelong risks of atrial myopathy affect the later incidence of atrial fibrillation in older adults.