Genetic Predisposition To Thoracic Aortic Aneurysms/Dissections

描述(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。随着时间的推移，胸主动脉瘤逐渐扩大，最终导致急性主动脉夹层(TAAD)；如果在夹层前手术修复动脉瘤，可以防止过早死亡。TAAD以常染色体显性遗传方式遗传，在高达20%的TAAD患者(家族性TAAD)中表达可变，外显性降低。我们已经定位了FTAAD的五个染色体座位，并确定了五个基因，当突变时会导致FTAAD、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的突变是导致FTAAD的第七个基因。总体而言，这些基因的突变导致了大约20%的FTAAD。这些基因的识别为该病的发病机制提供了洞察力，突出了转化生长因子信号的异常和平滑肌收缩的紊乱是导致TAAD的因素。特定基因突变和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显著的临床异质性的基础。该项目的长期目标是确定导致FTAAD的基因并表征相关的表型。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，并确定这些家庭的临床表型。第二个目标是使用具有多个受影响成员的大家庭来绘制FTAAD的染色体基因座图。第三个目标是通过对大家族中受影响的亲属对进行外显子组测序来识别新的FTAAD基因，并将这些数据与连锁数据相结合，以有效地识别致病基因中的罕见变异。最后，将进行初步的病理、细胞和分子研究，以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认识，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.