Evaluation of First-Degree Relatives after Sudden Unexplained Death

项目摘要/摘要 不明原因猝死(SUD)是一种悲剧性事件，遗传性心律失常和心脏功能障碍 在大约30%的SUD病例中显示出这种情况。任何SUD事件都是一个戏剧性的信号 需要风险分层。对sud受害者的一级亲属的评估受到以下几个重要差距的限制 知识。首先，研究没有前瞻性地评估传播突变与从头突变的比率。 当分子尸检数据可用时，出现SUD病例。分子尸检对生存的意义 家庭成员取决于传播致病变异体的概率。第二，当分子尸检 如果不进行基因检测，对一级亲属来说，基因检测的价值仍然未知。更高的遗传风险 这一人群的分层将提高家庭诊断率并改善咨询。最后，遗传风险 在SUD家族中对致病和可能的致病变异进行分层取决于扩大 可能含有致病变异的基因。 该项目有三个具体目标：1)确定传播与新发病原体和 SUD中可能的致病变异；2)建立表型阳性亲属的全基因组产量评估 以及3)使用全基因组测序(WGS)来识别与以下相关的新的候选基因 苏德。这项拟议的研究是创新的，因为它使用了一个多州财团之间的密切合作伙伴关系 法医办公室和全国公认的临床和遗传学中心提供详细的 利用WGS对sud患者及其一级亲属的基因分型和表型进行评估。建议数 研究具有重要意义，因为该项目产生的数据将改善评估和管理 是sud患者的一级亲属。表型-基因型相关性将改善咨询。最后，目标明确 对事件风险最高的亲属的治疗应该会减少人群中进一步的猝死。 这个项目将推进候选人的总体培养目标，即成为一名独立的以患者为导向的人 研究人员，在影响SUD的遗传病方面具有专业知识。这笔拨款补充了候选人的 临床研究和公共卫生背景，通过提供集中培训的机会在遗传学和 生物信息学。通过WGS的课程学习和实践培训，应聘者将获得相关专业知识 并创建一个可扩展以测试其他假设的基因-表型数据库。候选人的 西北大学非常强大的指导团队和强大的翻译遗传资源 致力于韦伯斯特博士培训的研究为职业发展创造了巨大的机会，并将 为降低意外死亡后一级亲属死亡率的长期目标作出贡献 事件。

PROJECT SUMMARY / ABSTRACT Sudden unexplained death (SUD) is a tragic event and genetic disorders of heart rhythm and function have been demonstrated in approximately 30% of SUD cases. Any SUD event is a dramatic signal that first-degree relatives require risk stratification. Evaluation of first-degree relatives of a SUD victim is limited by several important gaps in knowledge. First, studies have not prospectively evaluated the rate of transmitted versus de novo mutations in SUD cases when data from molecular autopsy are available. The implications of molecular autopsy for surviving family members depends on the probability of transmitted pathogenic variants. Second, when molecular autopsy is not performed, the value of genetic testing remains unknown for first-degree relatives. Better genetic risk stratification in this population will improve family diagnosis rates and improve counseling. Finally, genetic risk stratification of pathogenic and likely pathogenic variants in families with SUD depends on expanding the list of genes that may harbor pathogenic variants. The project has three specific aims: 1) Determine the frequency of transmitted versus de novo pathogenic and likely pathogenic variants in SUD; 2) Establish the yield of whole genome evaluation in phenotype-positive relatives of a SUD victim; and 3) Use whole genome sequencing (WGS) to identify novel candidate genes associated with SUD. The proposed research is innovative because it uses a close partnership between a multi-state consortium of medical examiner's offices and a nationally-recognized clinical and genetics center to produce a detailed genotype and phenotype evaluation of both SUD victims and their first-degree relatives using WGS. The proposed research is significant because the data generated from this project will improve the evaluation and management of first-degree relatives of SUD victims. Phenotype-genotype correlations will improve counseling. Finally, targeting treatment to those relatives at highest risk for events should decrease further sudden death in the population. This project will advance the candidate's overall training goal, which is to become an independent patient-oriented researcher, with expertise in the genetic diseases that impact SUD. This grant supplements the candidate's background in clinical research and public health by providing an opportunity for focused training in genetics and bioinformatics. Through coursework and practical training in WGS, the candidate will achieve relevant expertise and create a genotype-phenotype database that can be expanded to test additional hypotheses. The candidate's exceptionally strong mentoring team at Northwestern University and the robust resources for translational genetic research dedicated to Dr. Webster's training create a tremendous opportunity for career development and will contribute to the long-term goal of decreasing mortality in first-degree relatives after a sudden unexpected death event.