One to two percent of human infants are born with congenital heart disease (CHD). The common anatomic forms of CHD include conotruncal defects (CTD) and patent ductus arteriosus (PDA). Studies in human families have shown that CTD and PDA tend to occur in a familial pattern, each type being specific to a particular family. While it is clear that genetic factors are important in the cause of these and other forms of congenital heart disease, the patterns of inheritance in human families tend to be complex, indicating that the combined effects of genes at more than one gene locus are involved. Despite the recent advances in mapping and. characterizing the human genome, progress in identifying the gene defects responsible for congenital heart diseases, including PDA and CTD, has been slow. This is because of the apparent complexity of inheritance, and the lack of large well-characterized families in which it can be assumed that all affected individuals have the same underlying genetic form of CHD or other study population with reduced genetic heterogeneity. Because the genetic instructions for development of the heart have been highly conserved during evolution, studies of naturally occurring congenital heart disease in other mammalian species can provide valuable clues to the genes underlying human CHD. Studies in dogs are of particular interest because dogs tend to have the same anatomic forms as in humans and with a similar frequency. In previous studies under this grant, the genetic transmission and embryologic defects in CTD and PDA were characterized, verifying that they are specific inherited traits. As in humans, the genetics of canine CTD and PDA initially appeared complex. However, subsequent studies provided evidence that the number of genes underlying each of these two forms of CHD is few. Using DNA collected from previous family studies of CTD and PDA and the developing canine genome map, we conducted a whole genome study of CTD. A region of linkage to CTD was found on each of 3 different canine chromosomes. The proposed further studies are aimed at identifying chromosome regions linked to PDA in separate families, and at exploring the gene content of the CTD- and PDA-linked regions to identify the defective genes involved. The findings are expected to aid in the discovery of the corresponding molecular genetic defects in humans, leading to advances in genetic counseling, prenatal diagnosis, and treatment of these common birth defects. ? ?
Showing the most recent 10 out of 21 publications
