Multiple mutations in genetic cardiovascular disease: a marker of disease severity?

Over the last 2 decades, major advances have been made in our identification and understanding of the genetic basis of cardiovascular disease. More than 40 cardiovascular disorders have now been identified to be directly caused by single-gene defects. These disorders span all aspects of cardiovascular disease and affect all parts of the heart structure. They include the inherited cardiomyopathies such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, and arrhythmogenic right ventricular dysplasia; primary arrhythmogenic disorders such as familial long-QT syndrome (LQTS) and Brugada syndrome; congenital heart diseases such as familial atrial septal defects; vascular diseases such as Marfan syndrome; and metabolic disorders such as familial hypercholesterolemia (FH). Until recently, these cardiac genetic disorders have been thought to involve only single-gene defects (ie, in an individual patient, 1 mutation in a single gene leads to a disease).