GENETIC STUDIES OF COMMON CONGENITAL HEART DEFECTS

常见先天性心脏缺陷的遗​​传学研究

• 批准号: 6536151
• 负责人: John William Belmont
• 金额: $ 87.73万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536151
• 关键词: clinical research; congenital heart disorder; echocardiography; family genetics; gene mutation; human subject; linkage mapping; quantitative trait loci

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.

该方案的目标是开展三类先天性心脏病(CHD)的遗传学研究：左室流出道梗阻(LVOTO)、偏侧畸形和心脏神经脊移位缺陷。左侧梗阻性病变约占所有先天性心脏病的14%，是新生儿总死亡率的重要因素。神经脊移位缺陷约占10%，左右不对称缺陷约占3%。尽管各种胚胎学、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，并不符合简单的遗传模式。这项提议的第一个具体目标将启动并扩展到LVOTO和侧向遗传学的链接方法。我们证实了在受影响儿童的父母中发生了显著的亚临床结构性心脏缺陷，支持了血流动力学严重缺陷反映阈值特征的模型。这些数据也与由于外显性降低的显性遗传而导致的一组病例相一致，事实上，我们已经确定至少19个LVOTO和35个偏侧性家系。对LVOTO父母的超声心动图研究表明，定量测量可能有助于描绘阈值下的责任分布。我们建议在LVOTO患者的父母和兄弟姐妹中进行更大范围和更全面的超声心动图评估。如果成功，这些数据将被用来通过同胞对和扩展家系研究设计来定位一个或多个影响左心发育的基因座(作为数量性状基因座-QTL)。第二个具体目标是在LVOTO和侧向缺陷的链接/关联分析中建立和测试案例/父三元组。我们收集了近500例分离病例的细胞和DNA样本，可用于病例对照研究和突变分析。受影响的孩子/父母三人组将用于使用传递不平衡(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，主要由小鼠基因敲除的表型暗示，将被检测。第三个具体目标将利用来自儿童充电协会的独特样本集。这种复杂的表型有很大可能是由毗连的基因缺失引起的。病例-父母三人组提供了一个绝佳的机会，可以在屏幕上测试极其密集的SNP标记图谱，以确定受影响者中是否存在预期的杂合性。识别与心脏缺陷有关的基因应能为孤立的心脏缺陷提供机械性的见解和候选基因。拟议的研究将提供一个基础，在此基础上推进对大量先天性心脏缺陷的遗传分析，以减少其发生并提供新的治疗机会。