Impact of molecular genetics on clinical cardiology.

The last decade has seen major progress towards understanding both the genetic defect and molecular pathogenesis of many monogenic disorders of the cardiovascular system including hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS) and Marfan syndrome (Table 1)1. Unlike the single gene disorders, however, the genetics of common diseases such as essential hypertension and coronary artery disease is proving much more difficult to unravel, although progress is being made as these diseases become the focus of intensive genetic research. We will review the impact of molecular genetics on clinical management in HCM, LQTS and Marfan syndrome, about which much information is available, to illustrate how molecular genetic knowledge is beginning to have a direct role in patient management. These three diseases are all autosomal disorders inherited in a dominant manner. Affected individuals are heterozygous: that is, they have one normal and one mutant copy of the gene. Offspring of affected individuals will therefore have a one in two risk of inheriting the mutation; they may, however, have a somewhat smaller risk of manifesting the disease as not all gene carriers are symptomatic (incomplete penetrance). HCM, LQTS and Marfan syndrome all have the potential to devastate families by sudden deaths. Previous studies suggest that dominant mutations associated with diseases of this severity do not survive for long enough to create marked founder effects (ie, apparently unrelated families descend from an unidentified common ancestor), so these conditions are likely to be evenly distributed among different populations worldwide2.