Genetic Predisposition To Thoracic Aortic Aneurysms/Dissections

 描述(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。如果已知一个人易患此病，则可启动临床治疗以防止这些死亡。我们和其他人已经确定，高达20%的没有遗传综合征的TAAD患者有TAAD(FTAAD)的家族史。我们估计，FTAAD的已知基因导致了大约30%的FTAAD家族的疾病。我们已经建立了FTAAD家系(有两个或两个以上成员受TAAD影响的620个家系)队列，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，在剩下的家族中，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，并迅速将这些发现转化为改善FTAAD家庭的临床护理和预防过早死亡。该项目的目标如下：(1)招募和鉴定更多的FTAAD家系，以及具有遗传触发的TAAD的家系，用于识别新的基因，并描绘与这些基因相关的临床特征和突变谱；(2)使用连锁数据和受影响亲属和三人组的完整外显子组和基因组测序，有效地识别新FTAAD基因中的罕见变异；(3)进行初始 对新的FTAAD基因进行病理学、分子和细胞生物学研究；(4)对单个罕见的变种和聚集在一个基因内的变异体进行病例对照关联研究，以确定新的FTAAD基因。总而言之，根据我们收集的队列和初步数据，我们唯一准备好识别新的FTAAD基因，这些数据表明我们可以识别FTAAD的新基因。发现FTAAD基因对于识别有主动脉夹层风险的个体、启动针对基因的临床治疗以及了解遗传性胸主动脉疾病的致病机制至关重要。

 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.