Genetic Predisposition To Thoracic Aortic Aneurysms/Dissections

 描述（由申请人提供）：胸主动脉瘤导致急性主动脉夹层（TAAD）可导致过早死亡。如果一个人是已知的倾向，临床管理可以开始，以防止这些死亡。我们和其他人已经确定，高达20%的TAAD患者没有遗传综合征有TAAD家族史（FTAAD）。我们估计，已知的FTAAD基因占约30%的FTAAD家族的疾病。我们建立了一个FTAAD家族队列（620个家族，其中有两个或更多成员受TAAD影响），已用于定位，鉴定和确认13个FTAAD基因，并建立与每个基因相关的临床表型。我们假设在其余的家族中有多个基因与疾病有关。该项目的总体目标是确定FTAAD的剩余基因，表征与新基因相关的表型，进行将突变基因与主动脉疾病联系起来的初步研究，并将这些发现迅速转化为改善临床护理和预防FTAAD家族的过早死亡。该项目的目标如下：（1）招募和表征额外的FTAAD家族，沿着遗传触发的TAAD家族，用于识别新基因，并描绘与这些基因相关的临床特征和突变谱;（2）使用受影响亲属和三人组的连锁数据和全外显子组和基因组测序，以有效地识别新FTAAD基因中的罕见变异;（3）初始化 新的FTAAD基因的病理学、分子和细胞生物学研究;（4）对单个罕见变异和基因内聚集的变异进行病例对照关联研究，以鉴定新的FTAAD基因。总之，我们是唯一的准备，以确定新的FTAAD基因的基础上，我们组装的队列和初步数据表明，我们可以确定FTAAD的新基因。发现FTAAD基因对于识别主动脉夹层风险个体和启动基因特异性临床管理以及了解遗传性胸主动脉疾病的因果机制至关重要。

 DESCRIPTION (provided by applicant): Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can cause premature deaths. If an individual is known to be predisposed, clinical management can be initiated to prevent these deaths. We and others have determined that up to 20% of TAAD patients without a genetic syndrome have a family history of TAAD (FTAAD). We estimated that the known genes for FTAAD account for disease in approximately 30% of FTAAD families. We have established a cohort of FTAAD families (620 families with two or more members affected by TAAD), which has been used to map, identify, and confirm 13 FTAAD genes and establish the clinical phenotype associated with each gene. We hypothesize that there are multiple genes responsible for disease in the remaining families. The overarching goal of the project is to identify the remaining genes for FTAAD, characterize the phenotype associated with novel genes, perform initial studies linking the mutant gene to aortic disease, and rapidly translate these findings into improved clinical care and prevention of premature deaths in FTAAD families. The aims of the project are the following: (1) recruit and characterize additional FTAAD families, along with families with genetically triggered TAAD, to be used to identify novel genes and delineate the clinical features and mutation spectrum associated with these genes; (2) use linkage data and whole exome and genome sequencing of affected relatives and trios to efficiently identify rare variants in novel FTAAD genes; (3) perform initial pathologic, molecular and cellular biology studies of novel FTAAD genes; (4) pursue case control association studies for single rare variants and variants aggregated within a gene to identify novel FTAAD genes. In summary, we are uniquely poised to identify novel FTAAD genes based on our assembled cohort and preliminary data indicating that we can identify novel genes for FTAAD. Uncovering FTAAD genes is crucial for identifying individuals at risk for aortic dissections and initiating gene-specific clinical management, as well as understanding the causal mechanisms of inherited thoracic aortic disease.