Genetics of Congenital Left-sided Heart Defects

描述（由申请人提供）： 申请人是一名临床遗传学研究员，具有丰富的临床经验。该计划的目标是通过研究生课程和指导研究，使他成为复杂疾病遗传解剖的独立临床研究员。具体课程将包括分子遗传学，遗传流行病学，研究设计和科学研究的道德行为。研究环境将是贝勒医学院，一个卓越的遗传研究中心。设施包括一个基因分型中心和一个测序中心附属于人类基因组计划。将对先天性心血管畸形（CCVM）的左心室流出道梗阻（LVOTO）亚组的遗传学进行指导研究。这一组占所有CCVM的约20%，是整体新生儿死亡率的重要贡献者。各种胚胎学、流行病学和细胞遗传学证据都指出遗传因素的重要性，但大多数病例是散发性的，表明遗传成分是复杂的，不符合简单的遗传模式。第一个具体目标是通过多重LVOTO家族和受累同胞对的连锁方法研究LVOTO遗传学。 第二个具体目标是通过超声心动图研究受影响病例的家庭成员，以寻找可能有助于绘制左心发育的数量性状基因座的定量测量。第三个具体目标是通过传递不平衡和似然比分析在关联研究中建立和检验受影响的儿童/父母三人组。将在300多个样本中检查主要由小鼠敲除表型提出的大约50个候选基因。第四个具体目标将是筛选通过文献中的动物模型鉴定的候选基因中的突变或通过我们以上的连锁和关联研究鉴定的突变。拟议的研究将启动申请人的独立研究生涯，为推进CCVM的遗传分析提供基础，旨在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.