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Genetic testing for inherited cardiac disease

Abstract

Over the past 2 decades, investigators in the field of cardiac genetics have evolved a complex understanding of the pathophysiological basis of inherited cardiac diseases, which predispose individuals to sudden cardiac death. In this Review, we describe the current status of gene discovery and the associations between phenotype and genotype in the cardiac channelopathies and cardiomyopathies. The various indications for genetic testing and its utility in the clinic are assessed in relation to diagnosis, cascade testing, guiding management, and prognosis. Some common problems exist across all phenotypes: the variable penetrance and expressivity of genetic disease, and the difficulty of assessing the functional and clinical effects of novel mutations. These issues will be of particular importance as the next-generation sequencing technologies are used by genetics laboratories to provide results from large panels of genes. The accurate interpretation of these results will be the main challenge for the future.

Key Points

  • Genetic testing for cardiac channelopathies and cardiomyopathies has developed substantially over the past 2 decades and is a potentially useful tool for clinicians, if used appropriately

  • Variable penetrance and expressivity of genetic disease are common and, combined with 'variants of unknown significance', complicate the interpretation of the results of genetic testing

  • The yield of genetic testing is never 100% for any given phenotype; as a diagnostic tool, therefore, genetic testing is largely limited to confirmation of disease

  • Genetic testing is, however, particularly useful in families in which a 'true' disease-causing mutation is found, and can be used to identify carriers and to reassure noncarriers

  • Genetic testing can be especially helpful in guiding therapy and assessing prognosis for long QT syndrome, but not in many other conditions

  • The future holds promise, but also challenges, for the interpretation of variants of unknown significance and the huge amount of genetic data that will be produced by next-generation sequencing technologies

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Figure 1: The main proteins involved in channelopathies.
Figure 2: Example electrocardiograms of various channelopathies.
Figure 3: The three main forms of cardiomyopathy.
Figure 4: The main proteins involved in cardiomyopathies.

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Acknowledgements

A. A. M. Wilde is also affiliated with the Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia.

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Wilde, A., Behr, E. Genetic testing for inherited cardiac disease. Nat Rev Cardiol 10, 571–583 (2013). https://doi.org/10.1038/nrcardio.2013.108

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