MOLECULAR GENETIC EPIDEMIOLOGY OF THREE CARDIAC DEFECTS

先天性心脏缺陷（CHDs）被认为是遗传和环境因素干扰心脏胚胎发生的结果。由于有多名成员患有房间隔缺损（asd）和房室管缺损（avcd）的家庭已经被描述过，并且室膜旁隔膜部分是由房室垫的形成完成的，因此本项目描述了asd、室膜旁隔膜缺损（VSDs）和avcd的遗传流行病学研究。爱荷华大学医院和诊所以及佛罗里达州杰克逊维尔的沃尔夫森儿童医院已经确定了三组受试者，每组受试者都有手术或超声心动图确诊的asd、vsd或avcd。第四组老年asd患者及其后代将在爱荷华州进行研究，因为据报道asd患者的后代心脏病复发率很高。提出的策略要求在爱荷华大学现有的分子遗传能力进行全基因组搜索，以寻找与这些缺陷有关的遗传位点。已经确定了asd、vsd和avcd的几个候选区域。此外，三种公认的综合征提供了额外的候选区域-唐氏综合征，Holt-Oram综合征和8p综合征。将根据这些区域内间隔较近的标记对受父母影响的儿童三人组进行基因分型，并使用连锁不平衡分析来缩小或排除这些候选区间。对三人组的全基因组关联研究将采用一种简约的技术，将来自相同冠心病表型的病例的DNA汇集起来，并与来自其父母的汇集DNA进行比较。将确定受影响儿童及其父母的等位基因频率分布显著不同的位点。当这样的位点被确定后，将使用高密度的短串联重复多态性标记进行染色体区域的精细定位，这些标记跨越每个候选间隔。这项研究有可能确定新的候选基因座，这些基因座是先天性心脏缺陷发展的危险因素。

(Adapted from the Applicant's Abstract) Congenital heart defects (CHDs) are thought to result from genetic and environmental factors that disturb cardiac embryogenesis. Because families with multiple members affected with atrial septal defects (ASDs) and atrioventricular canal defects (AVCDs) have been described, and the paramembranous ventricular septum is in part completed by the formation of the atrioventricular cushions, this project describes a genetic-epidemiologic study of ASDs, paramembranous ventricular septal defects (VSDs), and AVCDs. Three groups of subjects, each with surgically- or echocardiographically-confirmed diagnoses of ASDs, VSDs or AVCDs have been identified for study at the University of Iowa Hospitals and Clinics, and at Wolfson Children's Hospital in Jacksonville, Florida. A fourth group of older subjects with ASDs and their progeny will be studied at Iowa because of the reported high recurrence of heart disease in the offspring of subjects with ASDs. The strategy proposed calls upon the molecular genetic capacities available at the University of Iowa to carry out genome-wide searches for genetic loci involved in these defects. Several candidate regions have been identified for ASDs, VSDs and AVCDs. In addition, three well-recognized syndromes provide additional candidate regions - Down syndrome, Holt-Oram syndrome and 8p-syndrome. Parent-affected child trios will be genotyped for closely-spaced markers within these regions and linkage disequilibrium analysis will be used to narrow or exclude these candidate intervals. A genome-wide association study of the trios will employ a parsimonious technique in which DNA from cases with the same CHD phenotype will be pooled, and compared to the pooled DNA from their parents. Loci will be identified where the allele frequency distributions in the affected children and their parents are significantly different. When such loci are identified, a finer localization of the chromosomal area will be undertaken using a high-density set of short tandem repeat polymorphic markers that spans each of the candidate intervals. This study has the potential to identify new candidate loci which are risk factors for the development of congenital heart defects.