The genetics of congenital heart disease

There have been exciting strides made in the identification of genes causing congenital heart defects. Most congenital heart defects are genetically heterogeneous. This is exemplified by the multiple genetic loci that are associated with individual heart defects and the fact that for any known gene, mutations have only been found in the minority of the particular patient population studied. Clearly, studies on rare chromosome disorders that have a high frequency of congenital heart defects, in combination with genetic animal model systems, have proven to be a powerful approach for identifying disease-causing genes that are involved not only in rare syndromes, but in the general population as well. Interestingly, many of the genes identified thus far encode transcription factors involved in developmental pathways. In addition, at least two genes have been identified that encode ligands for receptors involved in developmental pathways. Finally, cell adhesion molecules have been implicated for having a role in cardiac development and possibly in causing congenital heart defects. As more disease-causing genes are identified, developmental pathways will be defined that may ultimately link regulatory genes to their downstream targets, which may lead to the identification of additional disease-causing genes. One such gene, fibroblast growth factor 8, appears to be a downstream target of TBX-1 and, therefore, may be another gene that can cause the defects that occur in DiGeorge syndrome. As cardiac developmental pathways are better defined, our current understanding of the etiologic mechanisms of congenital heart disease is likely to change. For example, although a common mechanism is believed to underlie left-sided obstructive lesions (ie, so-called flow defects), the genetic pathways linking both left and right heart defects, both of which occur in a single genetic syndrome such as Jacobsen syndrome, are unknown. Thus novel cardiac developmental pathways that will improve our understanding of cardiac development and the genetic basis of congenital heart disease remain to be elucidated. It is estimated that there are 1 million adults in the United States with congenital heart disease. As more genetic loci are identified for individual heart defects, this will lead to improved approaches for predicting recurrence in the offspring in this new generation of congenital heart disease survivors. For example, FISH can be performed by a clinical genetics laboratory at the time of amniocentesis to detect microdeletions, thereby providing early fetal genetic diagnosis. Hopefully, our understanding of genes causing congenital heart disease will translate into better therapies and, ultimately, prevention of this devastating set of disorders.