A rare KCNE1 polymorphism, D85N, as a genetic modifier of long QT syndrome

Background: The gene KCNE1 encodes the β-subunit of cardiac voltage-gated K+ channels and causes long QT syndrome (LQTS). LQTS is characterized by the prolongation of QT interval and lethal arrhythmias such as torsade de pointes (TdP). A KCNE1 polymorphism, D85N, has been shown to modify the phenotype of LQTS through a loss-of-function effect on both KCNQ1 and KCNH2 channels when co-expressed and reconstituted in a heterologous expression system. Methods: A screening for the D85N polymorphism was performed in 355 LQTS families with mutations in KCNQ1, KCNH2, or SCN5A. Among the probands who had a heterozygous status with the polymorphism, we focused on a family with a KCNH2 mutation (E58K), a N-terminal missense mutation, and examined the clinical significance of this polymorphism. We also conducted biophysical assays to analyze the effect of the polymorphism in mammalian cells. Results: In 355 probands, we found 14 probands (3.9%) who had a heterozygous compound status with the D85N polymorphism. In the family with a KCNE1-D85N polymorphism and a KCNH2-E58K mutation, the proband and her daughter carried both the KCNH2 mutation and the KCNE1-D85N polymorphism. They experienced repetitive syncope and TdP. Two sons of the proband had either KCNH2-E58K mutation or KCNE1-D85N, but were asymptomatic. Biophysical assays of KCNE1-D85N with KCNH2-E58K variants produced a larger reduction in the reconstituted IKr currents compared to co-expression with wild-type KCNE1. Conclusions: The KCNE1-D85N polymorphism modified the clinical features of LQTS patients

Genetic screening of KCNJ8 in Japanese patients with J-wave syndromes or idiopathic ventricular fibrillation

Background: J-point elevation has been demonstrated to be associated with ventricular fibrillation (VF) and has been proposed as a cause of the J-wave syndrome (JWS). A mutation of KCNJ8, S422L, was reported as a culprit gene. This study aimed to determine the prevalence of KCNJ8 mutations in a Japanese population with JWS or idiopathic VF (IVF). Methods: A total of 230 probands with JWS and IVF underwent genetic screening of KCNJ8. To analyze and compare clinical and electrocardiographic characteristics, the probands were divided into 4 groups: Brugada (Br) pattern only, early repolarization (ER) pattern only, Br and ER patterns, and true IVF. Results: The results of the genetic analysis revealed no S422L or other KCNJ8 mutations and indicated no significant difference between the groups. Conclusion: The KCNJ8 mutation showed no association with JWS or IVF among our Japanese patients