Genetics of congenital heart diseases in syndromic and non-syndromic patients: new advances and clinical implications

Congenital heart defects (CHDs) are the most common birth defects in humans and over the last 20 years significant progress has been made in the understanding of the molecular and genetic determinants of an increasing number of CHDs. Fundamental to this progress has been the contribution of five fields of research: the epidemiological results of the Baltimore-Washington Infant Study (BWIS); the pathogenetic classification introduced by Clark; the Human Genome Project; genotype-phenotype correlation and familial recurrence studies; and transgenic animals. The recently advanced cytogenetic techniques can now detect subtle rearrangements in chromosomes, which may be overlooked by standard methods and, more recently, molecular instruments such as linkage analysis and positional cloning are being used to identify genes causing Mendelian monogenic syndromes with CHDs, such as Holt-Oram, Ellis-van Creveld and Noonan/LEOPARD syndromes. Finally, useful information is yet available with regard to genes causing isolated CHDs in individuals who do not have a genetic syndrome (an example is the mutation of NKX2.5 and GATA4 genes causing atrial septal defect). The future perspectives for the genetics of CHDs will involve three fields of interest: diagnosis; therapy; and prognosis.