Closer Look at Genetic Testing in Long-QT Syndrome

Abstract

Increasingly affordable sequencing has led to an explosion of DNA diagnostics and has fueled the hope for a genetic revolution in medicine. The popular vision is of definitive prediction of lifetime risk for a broad range of conditions from the primary analysis of each individual’s genomic sequence.1,2 The resultant panel of sequence variants will define the specific traits to which an individual is susceptible, triggering the institution of preventive measures or targeted therapies. Efficacy and safety will be largely assured for each of the chosen interventions. However, with the potential exception of pharmacogenetic studies in which the molecular targets are known, robust genotype-phenotype correlations are remarkably sparse and, in most instances, simply inadequate for rigorous risk prediction.3 Although genetics has transformed our understanding of the biology of disease, on closer examination it is not immediately evident when the “genomic revolution” will be realized as currently conceived for many cardiovascular conditions.3,4 Articles see pp 1752 and 1761 Nothing tests the tools of clinical risk prediction quite like sudden death.5 The difficulties encountered in the clinical application of genetic data, even in inherited conditions such as the long-QT syndrome (LQTS), in which the transmitted risk of sudden death is several hundred-fold greater than that in the general population, highlight some of the hurdles that must be overcome if DNA diagnosis is ever to transform cardiovascular medicine. Genetic testing for LQTS has been commercially available for several years, but a critical analysis of the clinical utility of test results reveals a rather mixed picture (see the Table).4 View this table: Table. Utility of LQTS Genetic Testing Genetic testing is commonly performed in those with a family history of LQTS and a known mutation, yet often the rationale is debatable. Individuals meeting the clinical criteria for LQTS in such families have …