MOLECULAR GENETIC EPIDEMIOLOGY OF THREE CARDIAC DEFECTS

先天性心脏病(CHD)被认为是由干扰心脏胚胎发育的遗传和环境因素造成的。由于房间隔缺陷(ASD)和房室管缺陷(AVCDs)的多成员家系已被描述，而膜旁室间隔部分是由房室垫的形成完成的，本项目描述了ASD、膜旁室间隔缺陷(VSD)和AVCDs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，每一组都经手术或超声心动图确诊为ASDS、VSD或AVCDs。第四组患有自闭症的老年受试者及其后代将在爱荷华州进行研究，因为据报道，自闭症受试者的后代心脏病复发率很高。该战略建议利用爱荷华大学现有的分子遗传能力，在全基因组范围内搜索与这些缺陷有关的遗传位点。已经为ASD、VSD和AVCD确定了几个候选区域。此外，三种公认的综合征提供了额外的候选区域-唐氏综合症、Holt-Oram综合征和8P综合征。受父母影响的儿童三人组将在这些区域内进行近距离标记的基因分型，并将使用连锁不平衡分析来缩小或排除这些候选间隔。这三人的全基因组关联研究将采用一种简约的技术，将具有相同CHD表型的病例的DNA汇集在一起，并与他们父母汇集的DNA进行比较。将确定在受影响儿童及其父母中等位基因频率分布显著不同的基因座。当识别出这样的基因座时，将使用跨越每个候选区间的一组高密度短串联重复多态标记对染色体区域进行更精细的定位。这项研究有可能确定新的候选基因，这些基因是先天性心脏病发生的危险因素。

(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.