Genotyping Has a Minor Role in Selecting Therapy for Congenital Long-QT Syndromes at Present

Abstract

Genotyping has led to enormous advances in understanding the phenotype and clinical course of the congenital long-QT syndromes (LQTS). In the most common LQTS forms, LQT1, LQT2, and LQT3, genotyping a clearly affected person in each family provides the ability to easily identify family members with reduced penetrance of the QTc and symptoms phenotypes, thus, providing also the opportunity to prevent sudden death and cardiac arrest by administering presymptomatic therapy. Response by Moss and Goldberg see p 227 The role of genotyping in selecting the therapy for LQTS is, on the other hand, unclear. Data from the literature and from the Salt Lake City LQTS database will be presented to show that genotyping has only a minor role in selecting therapy for LQTS. The discussion will primarily address the LQT1, LQT2, and LQT3 forms (caused by mutations of the LQT1, 2, 3, 5, and 6 genes)1 and the rare LQT4, LQT7, and LQT8 forms will be discussed briefly, and because so little is known about the new LQT9-11 forms they are not ready for a discussion of genotyping for therapy decisions. The pleural term “Long-QT syndromes” is indeed now very appropriate because of the diversity (both molecular and phenotype) of the conditions caused by the 11 accepted or proposed LQTS genes. The idea of genotype-based therapy has been discussed for some time, being encouraged by the experimental findings with mexiletine and flecainide in LQT3 and potassium supplementation in LQT2, plus other laboratory findings.2–8 The concept has received additional attention recently as some details outlining the complexity of the molecular substrate of LQTS are being reported.9–18 There are several concepts that are important for the discussion of this controversy. First, what we really want to accomplish by treatment is to prevent sudden death and aborted cardiac arrest. Most …