The molecular genetics of cardiovascular disease

The following consideration of this past year's published studies uses the cited reports as important examples of the ongoing characterization of the molecular basis of cardiac disease and the process of cardiac development. Mutations in cardiac troponin T and alpha-tropomyosin have been identified in familial hypertrophic cardiomyopathy, as have new beta-myosin heavy chain gene mutations. The general relation between beta-myosin heavy chain gene mutations that produce a charge change versus conservative amino acid replacements and sudden death remains unresolved. New fibrillin 1 gene mutations have been identified in patients with Marfan syndrome, the neonatal form of Marfan syndrome, and ectopia lentis. The same mutation is rarely found in more than one family. The association of supravalvar aortic stenosis and elastin gene mutations was further strengthened. The complexity of the relation between dystrophin mutations and the cell-specific loss of dystrophin expression can result in patients having cardiomyopathy and no myopathy. X-chromosome inactivation was shown to be the basis of cardiomyopathy in women with a single mutated dystrophin allele. New candidate genes that control cardiac morphogenesis and myocyte differentiation were proposed. New evidence to support 22q11 microdeletions as a common basis of nonsyndromic conotruncal malformations was published. These studies represent an important beginning. Although mutant genes have been recognized in affected individuals with various syndromes and congenital cardiac abnormalities, our understanding of how a genotype yields a given phenotype remains to be established.