Genetic Predisposition To Thoracic Aortic Aneurysms/Dissections

导致急性主动脉夹层（TAAD）的胸主动脉瘤是导致过早死亡的原因之一。 在工业化国家，死亡率高达8%。识别 有TAAD风险的个体允许进行医疗管理，以防止由于 解剖我们确定，高达20%的TAAD患者没有已知的遗传综合征， 有TAAD家族史，主要以常染色体显性方式遗传 （称为遗传性胸主动脉疾病，HALST）。我们建立了一个群体， (842有两个或两个以上TAAD成员的家庭），并使用该队列来确定新的 基因受阻。我们实验室和其他实验室的定位克隆和候选基因方法 成功鉴定了18个HSP 70基因。我们假设有多个改变的 基因尚未确定，破坏已知的和新的分子途径负责 胸主动脉疾病，并负责疾病的未解决的障碍家庭。 该项目的首要目标是确定HSP 70的剩余基因， 表征与这些新基因相关的表型，进行初始分子生物学研究， 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主动脉夹层导致的过早死亡 在哈塞尔家族。建议的目标是：（1）招募和鉴定额外的障碍物 家族可用于鉴定新基因，并描述临床特征和突变 与新基因相关的谱;（2）对HSP 70病例进行外显子组/基因组测序 并使用遗传策略来识别新的基因，包括分离罕见的变异， 受影响的亲属和三人组（受影响的先证者和未受影响的父母）和负担分析; 使用来自HSP 70家族和对照的外显子组数据， 鉴定新的疾病基因;（4）对新的疾病基因进行初步的分子和细胞生物学研究。 抑制基因，以确认突变基因和胸主动脉疾病之间的联系。在 总之，我们是唯一准备确定新的阻碍基因使用我们的组装队列 并提出了经验证的新策略来鉴定其他HSP 70基因。 发现HSP 70基因对于识别有主动脉夹层风险的个体至关重要， 启动基因特异性临床管理，以防止由于解剖导致的过早死亡。

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.