Abstract 2249: Overlap Between LQT3 and Brugada Syndrome: Clinical Features in a Common Mutation and Underlying Biophysical Mechanisms

Introduction: Features of the Brugada syndrome (BrS) have been sporadically reported in type-3 long QT syndrome (LQT3). However, it is not clear whether such phenotypic overlap is determined by the biophysical properties of the mutant channel, or by other factors such as co-inherited genetic variations, gender, or ethnicity. To address this question, we report here the clinical features and biophysical properties of a single SCN5A mutation, E1784K, identified in multiple families of diverse ethnicities. Methods and Results: Among 37 LQT3 families (Asian 20, Caucasian 17) enrolled in 6 referral centers, 11 (30%) were carriers of E1784K, with a total of 33 mutation carriers (15 men, 18 women, 26±20 years; mean±SD). Two probands were the victims of sudden cardiac death. The LQT3 phenotype was highly penetrant: 30/33 (90.9%) mutation carriers had abnormally long QT intervals (carriers: QTc= 484±32 ms, n=33; non-carriers: QTc= 402±31 ms, n=21; p<0.001; mean±SD). In addition, 13/33 carriers (39%) showed sinus node dysfunction, and a diagnosis of BrS was established in 7/33. Four of five carriers exhibited coved-type ST elevation after class IC drug challenge. E1784K channels heterologously expressed in tsA201 cells in the presence of β 1 subunit showed late Na current characteristic of LQT3. In addition, E1784K displayed properties seen with other mutations sporadically reported to generate a mixed clinical phenotype (1795insD, ΔKPQ, ΔK1500): a large (−15.0 mV) negative shift in the voltage-dependence of inactivation (V 1/2 : wild type= −86.8±1.1 mV, n=25; E1784K= −101.8±1.3 mV, n=17; p<0.001, mean±SE), and a marked (7.5-fold) increase in flecainide affinity for rested channels (IC 50 : wild type= 150.3 μM, E1784K= 20.4 μM). These properties are not reported with T1304M, an LQT3 mutation that has not been associated with BrS. Conclusions: E1784K is a highly prevalent SCN5A mutation in different ethnicities, producing LQT3 as well as BrS and sinus node dysfunction. In vitro studies suggest that a negative shift of steady-state inactivation and enhanced channel inhibition at rest by class IC drugs identify LQT3 mutations that can generate such a mixed phenotype. Class IC drugs should be avoided in patients with LQT3 mutations displaying these behaviors.