QT Interval Determinant: Mutations, Rare Variants, or Single-Nucleotide Polymorphisms?

Abstract

Long-QT syndrome (LQTS) is typically characterized by QT interval prolongation on ECG associated with syncope or sudden cardiac death in young individuals when prolongation of the QT interval induces torsade de pointes, a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation.1 LQTS is characterized by mutations in several ion channel genes. Although >10 susceptible genes have been identified, KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) are the most common LQTS genes, accounting for ≈90% of all genotype-positive cases. Only <5% of cases are diagnosed as LQT4~15, and 20% to 30% of cases remain genetically elusive. In the past 2 decade, lots of LQTS clinical databases have revealed genotype–phenotype correlations in the 3 major LQTS (LQT1~3) subtypes and have indicated that the genotype, together with QTc interval, age, and sex, is a determinant of arrhythmic risk and response to medication therapy.2 Furthermore, not only genotype but also mutation site–specific differences in arrhythmic risk could be reported in LQT1 and LQT2.3,4 See Article by Rosenberg et al However, as in most Mendelian disorders, patient management is complicated by the variability in disease severity among LQTS mutation carriers.5 Even in the same mutation, for example, KCNQ1 -A341V, mutation carriers had a wide range of QTc values (406–676 ms), and 12% of individuals had a normal QTc (≤440 ms).6 Furthermore, in addition to the LQTS-causing gene mutations, other genetic polymorphisms, such as NOS1AP , KCNE1 -D85N may affect the QT …