doi: 10.1161/CIRCULATIONAHA.109.192658
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(Circulation. 2009;120:1743-1744.)
© 2009 American Heart Association, Inc.
Clinical Summaries
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
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Genetic Testing for Long-QT Syndrome: Distinguishing Pathogenic Mutations From Benign Variants |
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Genetic testing for congenital long-QT syndrome has become an established part of the clinical armamentarium for physicians encountering patients with a personal or family history of ventricular tachyarrhythmias and sudden cardiac death. However, the presence of a positive genetic test result must be reviewed carefully. Most mutations identified in cases of long-QT syndrome are novel missense mutations and thus must be distinguished as either background noise or function-altering/disease-causing mutations. Specifically, even in the general healthy population, genetic variation, including known polymorphisms and novel, rare variants, may be demonstrated. Thus, the presence of a genetic mutation should be interpreted as a probabilistic measure of likelihood of disease rather than as a binary indicator of its presence or absence. This work indicates that mutation type, mutation location, and ethnic-specific background rates are critical factors in predicting the pathogenicity of novel mutations. However, in certain cases, distinguishing pathogenic mutations from rare variants may not be possible without additional functional characterization or linkage analyses. Although mutations localizing to certain specialized regions may be expected with high probability to be disease causing, mutations in other regions should be seen as variants of uncertain significance and should be interpreted in the clinical context and lead to further investigation rather than prompting assumption of disease presence and resulting therapeutic interventions. This classification of genetic test results as a probabilistic rather than absolute measure of disease causation has potential implications when counseling patients, especially as genetic testing becomes less expensive, more easily available, and more commonly used. These
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