Genetic Predisposition To Thoracic Aortic Aneurysms/Dissections

导致急性主动脉夹层(TAAD)的胸主动脉瘤是早产的原因之一 在工业化国家，高达8%的猝死是由死亡造成的。识别 有TAAD风险的个人可以进行医疗管理，防止因以下原因而死亡 解剖。我们确定，高达20%的没有已知遗传综合征的TAAD患者 有TAAD家族史，主要以常染色体显性遗传方式遗传 (称为遗传性胸主动脉疾病，HTAD)。我们建立了一个HTAD家族队列 (842个有两个或更多成员患有TAAD的家庭)，并使用这个队列来识别新的 HTAD基因。我们实验室和其他实验室的位置克隆和候选基因方法 成功鉴定出18个HTAD基因。我们假设有多个改变 基因尚未被识别，扰乱了已知和新的分子通路 用于胸主动脉疾病，并对未解决的HTAD家族的疾病负责。 该项目的首要目标是确定HTAD的剩余基因， 鉴定与这些新基因相关的表型，进行初始分子 将突变基因与主动脉疾病联系起来的研究，并迅速将这些发现转化为 改善临床护理和预防因主动脉夹层导致的过早死亡 在HTAD家族中。建议的目标是：(1)招募和鉴定更多的HTAD 用于识别新基因并描绘临床特征和突变的家系 与新基因相关的谱；(2)对HTAD病例进行外显子组/基因组测序 并使用遗传策略来识别新基因，包括分离稀有变异 受影响的亲属和三人(受影响的先证者和未受影响的父母)和负担分析；(3) 采用机器学习方法，使用来自HTAD家族和对照的外显子数据来 鉴定新的致病基因；(4)对新基因进行初步的分子和细胞生物学研究 HTAD基因，以确认突变基因与胸主动脉疾病之间的联系。在……里面 总结，我们唯一准备利用我们组装的队列来识别新的HTAD基因 并提出了经过验证的和新颖的策略来识别更多的HTAD基因。 发现HTAD基因对于识别有主动脉夹层和主动脉夹层风险的个体至关重要 启动针对基因的临床治疗，以防止因夹层导致的过早死亡。

Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) are a cause of premature deaths, responsible for up to 8% of sudden deaths in industrialized countries. Identifying individuals at risk for TAAD allows for medical management that prevents deaths due to dissections. We determined that up to 20% of TAAD patients without a known genetic syndrome have a family history of TAAD, which is inherited primarily in an autosomal dominant manner (termed heritable thoracic aortic disease, HTAD). We established a cohort of HTAD families (842 families with two or more members with TAAD) and used this cohort to identify novel HTAD genes. Positional cloning and candidate gene approaches by our lab and others have successfully identified 18 genes for HTAD. We hypothesize that there are multiple altered genes yet to be identified, disrupting known and novel molecular pathways responsible for thoracic aortic disease, and responsible for disease in the unsolved HTAD families. The overarching goal of the project is to identify the remaining genes for HTAD, characterize the phenotype associated with these novel genes, perform initial molecular studies linking the mutant gene to aortic disease, and rapidly translate these findings into improved clinical care and prevention of premature deaths due to aortic dissection in HTAD families. The proposed aims are: (1) Recruit and characterize additional HTAD families to be used to identify novel genes, and delineate the clinical features and mutation spectrum associated with new genes; (2) Pursue exome/genome sequencing on HTAD cases and use the genetic strategies to identify novel genes, including segregation of rare variants in affected relatives and trios (affected proband and unaffected parents) and burden analyses; (3) Pursue a machine-learning approach using exome data from HTAD families and controls to identify novel disease genes; (4) Perform initial molecular and cellular biology studies of novel HTAD genes to confirm a link between the mutant gene and thoracic aortic disease. In summary, we are uniquely poised to identify novel HTAD genes using our assembled cohort and are proposing both proven and novel strategies to identify additional HTAD genes. Uncovering HTAD genes is crucial for identifying individuals at risk for aortic dissections and initiating gene-specific clinical management to prevent premature death due to dissections.