The American Heart Association (AHA) has issued a report on the impact of laboratory molecular diagnosis of three genetically transmitted cardiovascular diseases: hypertrophic cardiomyopathy, long-QT syndrome and Marfan syndrome. The report notes that the present role for the DNA diagnosis of cardiovascular diseases is largely confined to research-oriented genotyping, with only limited access to laboratory genetic analysis.

The report, designated by the AHA as a “medical/scientific statement,” was developed by the AHA Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science. It is published in the October 6, 1998, issue of Circulation.

According to the report, the need to examine the role of a molecular diagnosis in genetic cardiovascular disease relates to advances in the understanding of both the phenotypic and genotypic expressions of several genetically transmitted, nonatherosclerotic cardiovascular diseases. Although molecular laboratory techniques continue to be used primarily in research-oriented settings, such technologic advances have led to the identification of new subgroups of genetically affected individuals who do not exhibit the conventional manifestations of the cardiovascular disease. The AHA selected the three most common familial cardiovascular diseases for which gene defects have been identified: hypertrophic cardiomyopathy, long-QT syndrome and Marfan syndrome. All three of these diseases are associated with autosomal dominant inheritance and a risk of sudden cardiac death.

Discussed in the report are the clinical diagnosis (phenotype) and molecular diagnosis (genotype) of each of these diseases as well as conclusions that can be drawn from available data. Also discussed are some of the ethical questions that arise with genetic testing.

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy has been found to be caused by mutation in any one of five genes that encode proteins of the cardiac sarcomere: β-myosin heavy chain, cardiac troponin T, troponin I, α-tropomyosin and cardiac myosin-binding protein C. Data suggest that approximately 35 percent of cases of familial hypertrophic cardiomyopathy may be caused by mutations in the β-myosin heavy chain gene. Genetic testing in selected pedigrees has shown that DNA-based diagnosis is capable of identifying a greater number of children and adults with a preclinical diagnosis of hypertrophic cardiomyopathy.

The report notes that hypertrophic cardiomyopathy is readily established by clinical examination, including two-dimensional echocardiography. The lack of left ventricular hypertrophy is uncommon in genetically affected individuals. According to the report, the lack of phenotypic expression is largely confined to individuals with non-myosin mutations. Molecular studies may in the future be useful in ambiguous cases, such as in patients with a borderline or modest increase in left ventricular wall thickness, including some trained athletes with ventricular hypertrophy, and in patients with systemic hypertension who are suspected of having hypertrophic cardiomyopathy.

Long-QT Syndrome

Long-QT syndrome is characterized by abnormal prolongation of ventricular repolarization, which is manifested on electrocardiography (ECG) by lengthening of the QT interval. This abnormality is most easily identified in lead II or V₁, V₃ or V₅. While long-QT syndrome often remains unrecognized, it can be a cause of death in young persons, including competitive athletes. Genotypic studies have identified four mutant genes responsible for the development of long-QT syndrome. These genes encode proteins of the cardiac ion channels.

According to the report, the difficulties in identifying ECG evidence of long-QT syndrome suggest that there may be a significant role for DNA diagnosis in this disease. In addition, studies suggest that clinical diagnosis may be uncertain on the basis of the QTc measurement in as many as 50 percent of family members. However, the heterogeneity of the disease—four or more genes and many mutations—may hamper genetic screening for this disease.

Marfan Syndrome

The variabilities in how Marfan syndrome is expressed have led to the development of comprehensive diagnostic criteria for this disease (see the accompanying table). The primary genetic defect responsible for Marfan syndrome was first described in 1991. It resides in FBN1 gene, which is localized to the long arm of chromosome 15 encoding the connective tissue protein fibrillin-1. According to the AHA statement, phenotype–genotype correlations have not emerged in clinical studies, largely because of the array of mutations in the fibrillin gene. Genetic testing in Marfan syndrome is currently regarded as only an adjunct to diagnosis.