Genetic Predisposition To Thoracic Aortic Aneurysms/Dissections

描述（由申请人提供）：胸主动脉瘤和夹层是影响胸主动脉的主要疾病，也是美国发病率和死亡率的常见原因。胸主动脉瘤随着时间的推移逐渐增大，最终导致急性主动脉夹层（TAAD）；如果动脉瘤在解剖前进行手术修复，可以预防过早死亡。TAAD以常染色体显性方式遗传，在高达20%的TAAD患者中具有可变的表达和降低的外显率（家族性TAAD）。我们绘制了FTAAD的5个染色体位点，并确定了5个突变导致FTAAD的基因：FBN1、TGFBR2、TGFBR1、ACTA2和MYLK；其他研究人员已经确定MYH11是第六个基因。最近，基于家族的外显子组测序发现SMAD3突变是导致FTAAD的第七个基因。总的来说，这些基因的突变导致了大约20%的FTAAD。这些基因的鉴定提供了对该疾病发病机制的深入了解，突出了异常转化生长因子-信号传导和平滑肌收缩中断是导致TAAD的因素。特定基因突变与相应表型之间的相关性揭示了与每个基因相关的独特特征，因此建议FTAAD家族的疾病管理应基于特定的遗传缺陷。我们假设有多个基因与家族性TAAD有关，这种遗传异质性是FTAAD显著临床异质性的基础。该项目的长期目标是确定导致FTAAD的基因并表征相关表型。第一个目标是招募有两个或更多成员患有TAAD的家庭，收集样本，并表征这些家庭的临床表型。第二个目标是利用有多个受影响成员的大家庭来绘制FTAAD的染色体位点。第三个目标是通过对来自大家族的受影响亲属对进行外显子组测序，并将这些数据与连锁数据相结合，有效地鉴定致病基因的罕见变异，从而鉴定出新的FTAAD基因。最后，初步的病理、细胞和分子研究将开始了解基因突变对主动脉功能的影响。通过这些研究，我们将提高对主动脉疾病病因的理解，并为家族性胸主动脉疾病的正确临床治疗提供关键数据。

DESCRIPTION (provided by applicant): Thoracic aortic aneurysms and dissections are the major diseases affecting the thoracic aorta and a common cause of morbidity and mortality in the United States. Thoracic aortic aneurysms progressively enlarge over time and ultimately lead to acute aortic dissections (TAAD); if the aneurysm is surgically repaired prior to dissection premature deaths can be prevented. TAAD is inherited in an autosomal dominant manner with variable expression and decreased penetrance in up to 20% of TAAD patients (Familial TAAD). We have mapped five chromosomal loci for FTAAD and identified five genes that when mutated cause FTAAD, FBN1, TGFBR2, TGFBR1, ACTA2, and MYLK; other investigators have identified MYH11 as a sixth gene. Recently, family-based exome sequencing identified mutations in SMAD3 as the seventh gene causing FTAAD. In total, mutations in these genes are responsible for approximately 20% of FTAAD. Identification of these genes has provided insight into the pathogenesis of the disease, highlighting aberrant transforming growth factor-¿ signaling and disrupted smooth muscle contraction as factors contributing to TAAD. Correlation between mutations in specific genes and the corresponding phenotype has revealed unique features associated with each gene, leading to recommendation that disease management in FTAAD families be based on the specific genetic defect. We hypothesize that there are multiple genes responsible for familial TAAD, and this genetic heterogeneity underlies the significant clinical heterogeneity observed in FTAAD. The long term goal of the project is to identify the genes that cause FTAAD and characterize the associated phenotype. The first aim is to recruit families with two or more members with TAAD, collect samples, and characterize the clinical phenotype of these families. The second aim is to map chromosomal loci for FTAAD using large families with multiple affected members. The third aim is to identify novel FTAAD genes through exome sequencing of affected relative pairs from large families and combining these data with the linkage data to efficiently identify rare variants in disease-causing genes. Finally, initial pathologic, cellular, and molecular studies will be done to begin to understand the effect of gene mutations on aortic function. Through these studies, we will improve understanding of the etiology of aortic diseases and provide data critical for the proper clinical management of familia thoracic aortic disease.