Genetics of Congenital Left-sided Heart Defects

描述(由申请人提供)： 申请人是临床遗传学研究员，有丰富的临床经验。这项提议的目标是让他通过研究生水平的课程和指导性研究，成为复杂疾病基因解剖方面的独立临床研究员。具体课程将包括分子遗传学、遗传流行病学、研究研究设计和科学研究的伦理行为。研究地点将设在贝勒医学院，这是一个卓越的基因研究中心。设施包括一个基因分型中心和一个附属于人类基因组计划的测序中心。将对先天性心血管畸形(CCVM)的左心室流出道梗阻(LVOTO)亚群的遗传学进行指导性研究。这一群体约占所有CCVM的20%，是新生儿总死亡率的重要贡献者。胚胎学、流行病学和细胞遗传学的各种证据表明遗传因素的重要性，但大多数病例是零星的，表明遗传成分复杂，不符合简单的遗传模式。第一个具体目的是用连锁方法研究多个LVOTO家系和患病同胞对的遗传。第二个具体目标是通过超声心动图研究受影响患者的家庭成员，寻找可能有助于定位影响左心发育的数量性状基因座的定量测量方法。第三个具体目标是通过传递平衡失调和似然比分析，在关联性研究中建立和检验受影响的儿童/父母三人组。大约50个候选基因，主要由小鼠基因敲除表型提出，将在300多个样本中进行检测。第四个具体目标将是筛选候选基因的突变，这些突变是通过文献中的动物模型确定的，或者通过我们上面的连锁和关联研究确定的。拟议的研究将使申请者开始独立的研究生涯，为推进CCVM的基因分析提供基础，以期减少其发生并提供新的治疗机会。

DESCRIPTION (provided by applicant): The applicant is a clinical genetics fellow with previous broad clinical experience. The goal of this proposal is for him to become an independent clinical investigator in the genetic dissection of complex diseases, through graduate level courses and mentored research. Specific courses will include molecular genetics, genetic epidemiology, research study design, and ethical conduct of scientific research. The research setting will be the Baylor College of Medicine, a center of excellence in genetic research. Facilities include a genotyping center and a sequencing center affiliated with the Human Genome Project. Mentored research will be performed on the genetics of the left ventricular outflow tract obstruction (LVOTO) subgroup of congenital cardiovascular malformations (CCVM). This group accounts for ~20% of all CCVM and are important contributors to overall neonatal mortality. Various lines of embryological, epidemiological, and cytogenetic evidence point to the importance of genetic factors, but most cases are sporadic, indicating the genetic components are complex and do not conform to a simple pattern of inheritance. The first Specific Aim is to investigate LVOTO genetics by the linkage approach on multiplex LVOTO families and affected sib pairs. The second Specific Aim is to study family members of affected cases by echocardiography, to search for quantitative measurements that might be useful for mapping quantitative trait loci contributing to left heart development. The third Specific Aim is to establish and test affected-child/parent trios in association studies by transmission dysequilibrium and likelihood ratio analyses. Approximately 50 candidate genes, suggested primarily by mouse knockout phenotypes, will be examined in over 300 samples. The fourth Specific Aim will be to screen for mutations in candidate genes identified through animal models in the literature or identified by our linkage and association studies above. The proposed studies will launch the applicant on an independent research career, providing a base on which to advance genetic analyses of CCVM with the aim to reduce their occurrence and provide new treatment opportunities.