Catch me if you can: tracking down the genetic origins of congenital heart disease

Abstract

Congenital heart disease (CHD) is the major cause of death in infants under 1 year of age. CHD kills more children than cancer and accounts for 25% of all birth defects, the single largest category of malformations.1 One newborn in 100 has CHD, and 1 newborn in 1000 will need surgery for CHD. Despite the impressive progress which has been made in deciphering the molecular events governing cardiogenesis, only a minority of heart defects are amenable to routine genetic diagnosis at the present time. Thus, the mechanism of disease remains elusive in the majority of patients, and classification and treatment of these malformations are based purely on morphological criteria. Which leads can then be followed to track the genetic basis of CHD? One classic approach, linkage analysis, requires relatively large families segregating the disease trait in a Mendelian fashion. Apart from variable expressivity and reduced penetrance of mutations, which can obscure the Mendelian character of disease, the relative rarity of these families makes their recognition and ascertainment a challenging task ( Table 1 ). Candidate gene approaches have been advocated based on the results of linkage studies, as well as based on the rapidly growing number of candidate genes which play important roles in embryonic heart formation. Clearly, some genotype–phenotype correlations have emerged from these studies—such as those linking mutations in NKX2.5 with atrial septal defects and atrioventricular conduction … *Corresponding author. Tel: +1 514 345 4931 ext 3244; fax: +1 514 345 4896. E-mail address: gregor.andelfinger{at}umontreal.ca