ETIOLOGY AND DEVELOPMENT OF CONGENITAL HEART DISEASE

先天性心脏病（CHD）包括许多不同的心脏解剖畸形，在活产婴儿中的发病率接近1%。在大多数受影响的儿童中，心脏缺陷是一种孤立的异常，不伴有其他器官系统的缺陷。相同的解剖形态往往发生在同一家庭的成员中，这表明潜在的遗传缺陷是解剖畸形的特异性。然而，由于遗传模式通常很复杂，并且缺乏已知具有特定解剖形式的冠心病成员的大型特征明确的人类家族，因此鉴定相关基因的进展一直很缓慢。对动物体内自然发生的冠心病的研究可以为克服这些困难提供有用的模型。和人类一样，狗的常见冠心病形式通常是孤立的缺陷。它们的临床和解剖特征以及相对频率与人类非常相似。导致冠心病的缺陷基因可能在两个物种中是相同的：特定的冠心病解剖形式聚集在特定的狗品种和家庭中，表明潜在的遗传缺陷是特定于冠心病解剖形式的。在这项资助下进行的犬冠心病的遗传和胚胎学研究证实，两种最常见的形式，圆锥体缺陷（CTD）和动脉导管未闭（PDA），是由干扰正常心脏发育特定过程的遗传缺陷引起的。在最初的研究中，犬CTD和PDA的遗传模式与人类一样复杂。然而，选择性近亲繁殖减少了遗传背景，随后孟德尔育种研究揭示了单基因效应的证据，使分离和表征相关基因成为可能。犬类基因组图谱的最新进展大大提高了这一努力取得成功的机会。拟议研究的长期目标是利用DNA样本和从犬CTD和PDA的广泛育种研究中获得的表型数据来绘制，克隆和表征这些形式的冠心病的基因。将使用微卫星全基因组连锁和候选基因研究。CTD与候选基因区域连锁的初步证据将继续研究。这些进展有望有助于发现人类CTD和PDA中相应的分子遗传缺陷，从而在遗传咨询、产前诊断方面取得进展，并有可能预防或改善易感胎儿中这些常见的出生缺陷。

Congenital heart diseases (CHD) include a number of different anatomic malformations of the heart, together having an incidence in live-born human infants approaching 1 percent. In most affected children, the heart defect is an isolated abnormality, unaccompanied by defects in other organ systems. The same anatomic form tends to occur in members of the same family, suggesting an underlying genetic defect that is specific for the anatomic malformation. However, progress in identifying the genes involved has been slow, owing to the often complex patterns of inheritance, and the lack of large well-characterized human families with members known to have a specific anatomic form of CHD. Studies of naturally-occurring CHD in animals can provide useful models to overcome these difficulties. The common forms of CHD in dogs, as in humans, are usually isolated defects. Their clinical and anatomic features and relative frequencies closely resemble those in humans. The defective genes underlying CHD may be the same in both species: Specific anatomic forms of CHD aggregate in particular dog breeds and families, showing that the underlying genetic defect is specific for the anatomic form of CHD. Genetic and embryologic studies of canine CHD conducted under this grant have confirmed that two of the most common forms, conotruncal defects (CTD) and patent ductus arteriosus (PDA), are caused by genetic defects that interfere with specific processes in normal heart development. In initial studies, patterns of inheritance of canine CTD and PDA were complex, as in humans. However, reduction of genetic background by selective inbreeding, followed by Mendelian breeding studies revealed evidence of single gene effects, making it feasible to isolate and characterize the genes involved. Recent progress in the development of the canine genome map greatly enhance the chances of success in this endeavor. The long term aims of the proposed studies are to utilize DNA samples and phenotypic data already obtained from extensive breeding studies of canine CTD and PDA to map, clone, and characterize the genes underlying these forms of CHD. Microsatellite whole genome linkage and candidate gene studies will be used. Preliminary evidence of linkage of CTD to candidate gene regions will be pursued. These advances are expected to aid in the discovery of the corresponding molecular genetic defects in human CTD and PDA, leading to advances in genetic counseling, prenatal diagnosis, and potentially to the prevention or amelioration of these common birth defects in predisposed fetuses.