KCNE5 modulates I(to), and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on I(to). Screening for KCNE5 variants is relevant for BrS or IVF.

Background-Drugs with I Kr -blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. Methods and Results-Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, Pϭ0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, PϽ0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. Conclusions-dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I Kr -blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome. (Circ Arrhythmia Electrophysiol. 2009;2:511-523.)Key Words: long-QT syndrome Ⅲ secondary Ⅲ drug Ⅲ electrophysiology Ⅲ ion channel C ongenital long-QT syndrome (cLQTS) is characterized by abnormally prolonged ventricular repolarization and familial inheritance, leading to polymorphic ventricular tachycardia (torsades de pointes [TdP]), causing sudden cardiac death. 1,2 In contrast, secondary long-QT syndrome can be induced by a variety of commercially available drugs, including antiarrhythmic drugs, antihistamines, antibiotics, Clinical Perspective on p 523and major tranquilizers. 3 In patients with drug-induced long-QT syndrome (dLQTS), after a washout period of the culprit drugs, the QT interval usually returns to within normal range. Genetic factors may underlie the susceptibility to drug-induced serious adverse reactions such as a long QT Received February 29, 2008; accepted July 6, 2009. (eg, drugs, hypokalemia, or bradycardia). Among the subjects, 20 probands had drug-induced cardiac events (10.2% of long-QT syndrome probands). Their clinical information was collected, including family history of sudden death age 30 years or younger and long-QT syndrome members, previ...

Background-Mutations of KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1, cause Andersen-Tawil syndrome (ATS), a disease exhibiting ventricular arrhythmia, periodic paralysis, and dysmorphic features. However, some KCNJ2 mutation carriers lack the ATS triad and sometimes share the phenotype of catecholaminergic polymorphic ventricular tachycardia (CPVT). We investigated clinical and biophysical characteristics of KCNJ2 mutation carriers with "atypical ATS." Methods and Results-Mutational analyses of KCNJ2 were performed in 57 unrelated probands showing typical (Ն2 ATS features) and atypical (only 1 of the ATS features or CPVT) ATS. We identified 24 mutation carriers. Mutation-positive rates were 75% (15/20) in typical ATS, 71% (5/7) in cardiac phenotype alone, 100% (2/2) in periodic paralysis, and 7% (2/28) in CPVT. We divided all carriers (nϭ45, including family members) into 2 groups: typical ATS (A) (nϭ21, 47%) and atypical phenotype (B) (nϭ24, 53%). Patients in (A) had a longer QUc interval [(A): 695Ϯ52 versus (B):643Ϯ35 ms] and higher U-wave amplitude (0.24Ϯ0.07 versus 0.18Ϯ0.08 mV). C-terminal mutations were more frequent in (A) (85% versus 38%, PϽ0.05). There were no significant differences in incidences of ventricular tachyarrhythmias. Functional analyses of 4 mutations found in (B) revealed that R82Q, R82W, and G144D exerted strong dominant negative suppression (current reduction by 95%, 97%, and 96%, respectively, versus WT at Ϫ50 mV) and T305S moderate suppression (reduction by 89%). Conclusions-KCNJ2 gene screening in atypical ATS phenotypes is of clinical importance because more than half of mutation carriers express atypical phenotypes, despite their arrhythmia severity. (Circ Cardiovasc Genet. 2012; 5:344-353.)