Abstract 19745: Brugada, Long QT and Cardiac Conduction Disease Overlap Syndrome Associated with the SCN5A-E1784K Mutation: Clinical Phenotype, Genetic Background and Potential Therapy
INTRODUCTION: Phenotypic overlap of type 3 long QT syndrome (LQT3), Brugada syndrome (BrS) and cardiac conduction disease (CCD) is observed with some SCN5A mutations. SCN5A-E1784K is the most common mutation associated with LQT3 and BrS. The present study examines the genotype-phenotype relationship in a 76 member European family carrying the SCN5A-E1784K mutation and the common polymorphism SCN5A-H558R.
METHODS: Clinical work-up and genetic analysis were performed following informed consent. Functional characterization was achieved by expression of the SCN5A variants in TSA201 cells. Peak (INa,P) or late (INa,L) sodium channel current was recorded using whole cell patch-clamp techniques.
RESULTS: A total of 35 family members (19 male and 16 female, mean age 29.8 ± 15.9 years) were evaluated. Thirteen patients died prior to initiation of the study. Twenty-eight family members refused genetic screening. Of the 35 genotyped family members, 17 were positive for the E1784K mutation in SCN5A (Table 1). All 17 displayed LQT intervals and either BrS or prolonged PR (as a surrogate of CCD). The presence of H558R did not significantly alter the phenotype of carriers positive for E1784K. Fourteen patients positive for E1784K underwent ICD implantation; 4 developed VF and received appropriate defibrillation shocks during a follow-up period of 8±3 months. Co-expression of SCN5A-E1784K and SCN5A-WT reduced INa,P to 70.03% of WT, shifted steady-state inactivation by -11.03mV and increased INa,L from 0.14% to 1.86% of INa,P. Similar changes were observed when E1784K was co-expressed with H558R. Ranolazine (10 µM) reduced INa,L of E1784K+WT by 65% without significantly affecting INa,P.
CONCLUSION: We demonstrate strong genotype-phenotype correlation and complete penetrance for LQTS and BrS/CCD in a large family harboring the E1784K missense mutation in SCN5A. Ranolazine, by virtue of its ability to suppress INa,L, may be an effective therapy for these cases of LQT3.
- © 2012 by American Heart Association, Inc.