Copy number variants and the genetic enigma of congenital heart disease.

Abstract

For years, many reasoned, perhaps not so naively, that genetics of congenital heart diseases (CHD) would be the last frontier in efforts to elucidate the genetic causes of cardiovascular disease. This impression was based on 2 main reasons. First, CHD seldom exhibits a clear familial inheritance pattern, as opposed to many single gene disorders. This is despite the strong evidence for familial aggregation of CHD and a higher risk of recurrence in the offspring, which denote a clear genetic cause.1,2 CHD are often sporadic or part of the aneuploidy syndromes with pleomorphic noncardiac phenotypes.1,3 Thus, an approach distinct from the genetic linkage analysis in large families, which was commonly applied to delineate the genetic basis of hereditary cardiovascular diseases such as cardiomyopathies and arrhythmia syndromes,4–8 was needed to define the genetic cause of CHD. Second, the extreme phenotypic assortment of CHD,3,9–11 which is far beyond phenotypic variability of single gene disorders, as well as the diversity of common complex diseases, such as coronary artery disease and systemic arterial hypertension. Consequently, it was difficult envisioning how apparently the simple phenotype of atrial septal defects and the complex phenotype of tetralogy of Fallot, which share no anatomic and physiological similarities, would causally share a common class of genetic networks, let alone arise from mutations in a single gene. Article, see p 884 Recent discoveries are transforming the landscape of molecular genetics of CHD and diluting the aforementioned antediluvian impression. The pioneering work of Basson et al12 and Schott et al13 in late 1990s led to the identification of loss-of-function mutations in TBX5 and NKX2-5 as causes of Holt–Oran syndrome and atrial septal defect, respectively. An intriguing finding was the assortment of clinical phenotypes in the mutation …