Elucidating the Genetic Cause of Congenital Heart Defects

Abstract

After completing this article, readers should be able to: 1. Understand the relationship between haploinsufficiency and autosomal dominant transmission. 2. Describe how incomplete penetrance and variable expressivity relate to the genetic analysis of congenital heart disease. 3. Delineate the current hypothesis for the cause of DiGeorge syndrome/velocardiofacial syndrome. 4. Understand the relationship between heterotaxy and congenital heart defects. 5. Discuss the possible role of folic acid in the development of congenital malformations. Congenital heart defects (CHD) are among the most common birth defects, with an incidence of 4 to 50 per 1,000 live births. CHD are the leading noninfectious cause of death in the first postnatal year. Although CHD long have been recognized as a component of complex genetic syndromes, a genetic cause for isolated CHD has been less obvious; the source of these defects generally has been believed to be multifactorial. In the past decade, however, molecular genetic studies have revealed that in many instances, CHD exhibits classic mendelian transmission and can be traced to discrete gene defects. The mendelian transmission of CHD may have been obscured by a variety of factors. As the genetic causes of CHD are being elucidated, substantial genetic heterogeneity (ie, mutations in different genes giving rise to the same phenotype) is becoming apparent. Another confounding factor in the genetic analysis of CHD has been the reduced penetrance of the mutant phenotypes, in which some individuals carrying the disease-causing mutations appear to be free of CHD. A third confounding factor has been variable expressivity. Clinically, CHD are classified anatomically (eg, conotruncal defects, atrial or ventricular septation defects). This classification has led to the bias that a particular genetic defect would result in a predictable anatomic defect. Although the resultant anatomic defects reflect the function of the mutated gene during cardiac development with many mutations, some genes impinge on several developmental …