Importance of Knowing the Genotype and the Specific Mutation When Managing Patients With Long-QT Syndrome

Long-QT syndrome (LQTS) is an inherited disorder with prolonged ventricular repolarization and an increased propensity to ventricular tachyarrhythmias of the torsade de pointes type that are responsible for arrhythmogenic syncope and sudden cardiac death.1 During the past 13 years, 10 different genotype forms of LQTS have been identified (LQT1–LQT10), with the most frequent clinical types (LQT1–LQT3) categorized as ion channelopathies.2 The remaining 7 infrequently occurring forms of LQTS (LQT4–LQT10) also affect myocellular ion channel currents either directly or indirectly, but LQT4–LQT10 make up less than 5% of the genotype-identified LQTS. To date, approximately 500 different LQTS mutations have been identified in the 10 LQTS genes, and cellular expression studies of these mutations have elucidated basic electrophysiological mechanisms responsible for the delayed repolarization and the manifest QT prolongation. Different LQTS genes affect different ion current mechanisms, and the clinical course of patients with LQT1–LQT3 genotypes have been shown to be quite different.3 In addition, different mutations on the same LQTS gene may produce different electrophysiological effects. For example, mutations involving the LQT1 gene are all associated with reduction in the repolarizing I Ks current, but the magnitude of the reduction in this current can vary considerably among the different LQT1 mutations.4 This variability in the electrophysiological effects of different mutations contributes to the variability in the risk of life-threatening cardiac events that are independent of the manifest QTc interval on the ECG. Thus, knowledge of the LQTS genotype and the associated specific mutations are useful in risk-stratifying individual patients for the selection of appropriate therapy for patient-specific risk-reduction.Response by Vincent see p 219 Because of the extensive literature that currently exists in LQTS, we will focus on the 3 common forms of LQTS (LQT1–LQT3) and related mutations to make our point that this information is useful …