Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type are characteristic of LQTS, while SQTS is characterized by shortened QT interval with tall peaked T-waves and a propensity for atrial fibrillation. Both syndromes represent a high risk for syncope and sudden death. LQTS exists as a congenital genetic disease (cLQTS) with more than 700 mutations described in 12 genes (LQT1-12), but can also be acquired (aLQTS). The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions. The latter includes Jervell and Lange-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations in five genes (SQTS1-5). The present mutation update is a comprehensive description of all known LQTS-and SQTS-associated mutations.

Background-The Brugada syndrome, an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in 4 different genes, leading to a loss of function in sodium and calcium channel activity.Although the transient outward current (I to ) is thought to play a prominent role in the expression of the syndrome, mutations in I to -related genes have not been identified as yet. Methods and Results-One hundred five probands with the Brugada syndrome were screened for ion channel gene mutations using single-strand conformation polymorphism electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 (MiRP2) was detected in 1 proband. The R99H mutation was found 4/4 phenotype-positive and 0/3 phenotype-negative family members.

Background Risk stratification in patients with type 3 long QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β-blocker therapy have not been studied previously in a large LQT3 population. Methods The study population included 406 LQT3 patients with 51 different sodium-channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired on patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CE) from age 1 to 41 years. Results 118 (30%) patients (41 males) experienced at least one CE (syncope, aborted cardiac arrest [ACA] or LQTS-related sudden death [SD]), and 20% suffered from LQT3-related ACA/SD. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent β-blocker therapy was associated with an 83% reduction in CE’s in females (p=0.015) but not in males (who had much fewer events), with a significant gender x β-blocker interaction (p=0.04). Each 10ms increase in QTc duration up to 500ms was associated with a 19% increase in CE’s. Prior syncope doubled the risk for life-threatening events (p<0.02). Conclusions Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CE’s. β-blocker therapy reduces this risk in females, but efficacy in males could not be conclusively determined due to low number of events.