GENETIC STUDIES OF COMMON CONGENITAL HEART DEFECTS

本提案的目的是开展三种先天性心脏缺陷（CHD）的遗传研究：左心室流出道梗阻（LVOTO）；侧边缺损，心脏神经嵴移位缺损。左侧梗阻性病变约占所有先天性心脏缺陷的14%，是导致新生儿总死亡率的重要因素。神经嵴移位缺陷占另外的10%，左右不对称缺陷约占3%。尽管各种各样的胚胎学、流行病学和细胞遗传学证据表明遗传因素的重要性，但大多数病例是零星的这一事实表明，遗传成分是复杂的，不符合简单的遗传模式。本提案的第一个具体目标将启动并扩展一种链接方法，以LVOTO和横向遗传学。我们已经证实，在受影响儿童的父母中显著发生亚临床结构性心脏缺陷，支持血流动力学严重缺陷反映阈值特征的模型。这些数据也与显性遗传导致外显率降低的病例一致，事实上，我们已经确定了至少19个LVOTO和35个侧性家族。超声心动图对LVOTO父母的研究表明，定量测量可能有助于描述阈值下的倾向性分布。我们建议对LVOTO患者的父母和兄弟姐妹进行更大、更全面的超声心动图评估。如果成功，这些数据将用于绘制一个或多个有助于左心脏发育的位点（作为数量性状位点- QTL），使用兄弟姐妹对和扩展谱系研究设计。第二个特定目标是在LVOTO和横向缺陷的链接/关联分析中建立和测试用例/父组。我们从近500个孤立病例中收集了细胞和DNA样本，可用于病例对照研究和突变分析。受影响的儿童/父母三人组将用于使用传播不平衡（TDT）和似然比（LRT）分析的连锁/关联研究，以及突变筛查。大约50个候选基因，主要由小鼠敲除的表型提示，将被检查。第三个具体目标将利用一个独特的样本集从儿童CHARGE协会。这种复杂的表型有很大的可能是由连续的基因缺失引起的。病例-亲本三人组提供了一个绝佳的机会，可以在筛查中检测极其密集的SNP标记图，以确定患者是否存在预期的杂合性。鉴定参与CHARGE的基因应该提供分离性心脏缺陷的机制见解和候选基因。拟议的研究将为推进大量先天性心脏缺陷的遗传分析提供基础，目的是减少其发生并提供新的治疗机会。

The goal of this proposal is to carry out genetic studies of three classes of congenital heart defects (CHD): left ventricular outflow tract obstruction (LVOTO); Laterality defects, and cardiac neural crest migration defect. Left-sided obstructive lesions account for approximately 14 percent of all congenital heart defects and are important contributors to overall neonatal mortality. Neural crest migration defects account for an additional 10 percent and defects of left-right asymmetry approximately 3 percent. Although various lines of embryological, epidemiological, and cytogenetic evidence point to the importance of genetic factors, the fact that most cases are sporadic indicates that the genetic components are complex and do not conform to a simple pattern of inheritance. The first Specific Aim of this proposal will initiate and extend a linkage approach to LVOTO and Laterality genetics. We have confirmed a significant occurrence of subclinical structural heart defects in the parents of affected children, supporting a model in which hemodynamically severe defects reflected a threshold trait. These data are also consistent with a supgroup of cases due to dominant inheritance with reduced penetrance and, indeed, we have ascertained at least 19 LVOTO and 35 Laterality families. Echocardiography studies in LVOTO parents suggest that quantitative measurement might be useful in delineating the liability distribution underlying the threshold. We propose to carry out a larger and more comprehensive evaluation of echocardiography in parents and sibs of LVOTO patients. If successful, these data will be used to map one or more loci contributing to left heart development (as quantitative trait loci - QTL) using sib pair and extended pedigree study designs. The second Specific Aim is to establish and test case/parent trios in Linkage/Association analyses in both LVOTO and Laterality defects. We have collected cell and DNA samples from almost 500 isolated cases that can be used in case-control studies and for mutation analyses. Affected-child/parent trios will be used in linkage/association studies using transmission disequilibrium (TDT) and likelihood ratio (LRT) analyses, as well as in mutational screening. Approximately 50 candidate genes, suggested primarily by the phenotypes of mouse knockouts, will be examined. The third Specific Aim will exploit a unique sample set from children with CHARGE Association. This complex phenotype has a substantial possibility of arising from a contiguous gene deletion. Case-parent trios offer an outstanding opportunity to test extremely dense SNP marker maps in a screen for absence of expected heterozygosity in the affecteds. Identification of genes involved in CHARGE should provide both mechanistic insights and candidate genes for isolated heart defects. The proposed studies will provide a base on which to advance genetic analyses of a substantial group of congenital heart defects with the aim of reducing their occurrence and providing new treatment opportunities.