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。 相同的解剖形式往往发生在同一家族的成员中，这表明解剖畸形特有的潜在遗传缺陷。 然而，由于通常复杂的遗传模式，以及缺乏具有已知具有特定解剖形式的CHD成员的大型良好特征的人类家族，因此在确定相关基因方面的进展缓慢。 对动物中自然发生的CHD的研究可以提供有用的模型来克服这些困难。 与人类一样，犬的CHD常见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。 先天性心脏病潜在的缺陷基因在两个物种中可能是相同的：先天性心脏病的特定解剖形式在特定的狗品种和家族中聚集，表明潜在的遗传缺陷对先天性心脏病的解剖形式是特异性的。 在该资助下进行的犬CHD的遗传学和胚胎学研究已经证实，两种最常见的形式，圆锥动脉干缺陷（CTD）和动脉导管未闭（PDA），是由干扰正常心脏发育中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，通过选择性近亲繁殖减少遗传背景，随后进行孟德尔育种研究，揭示了单基因效应的证据，使得分离和表征所涉及的基因是可行的。 犬基因组图谱的最新进展大大提高了这一奋进的成功机会。 拟议研究的长期目标是利用已经从犬CTD和PDA的广泛育种研究中获得的DNA样本和表型数据来绘制、克隆和表征这些形式的CHD的潜在基因。 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被追踪。 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，从而推动遗传咨询、产前诊断的进展，并可能预防或改善易患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.