Abstract 10583: A Novel Functional Variant, P.Gln419Pro, Residing Outside the SCN5A -Encoded Na V 1.5 Voltage-Sensing Domain Causes Multifocal Ectopic Purkinje-Related Premature Contractions

Abstract

Background: Multifocal ectopic Purkinje-related premature contractions (MEPPC), the most recent addition to the spectrum of SCN5A -mediated cardiac channelopathies, is characterized by frequent premature ventricular complexes (PVCs) originating from the Purkinje system, atrial arrhythmias, and a predilection for PVC-mediated dilated cardiomyopathy. MEPPC-causative variants tend to cluster within the voltage sensing domain (VSD) of Na v 1.5. Objective: To describe the clinical and cellular electrophysiological phenotype associated with a novel, putative MEPPC-causative SCN5A variant (p.Gln419Pro-SCN5A) that resides outside the VSD of Na v 1.5. Methods: p.Gln419Pro-SCN5A was identified in a 21-year-old male with a history of frequent, multifocal PVCs and atrial tachycardia. Subsequently, three p.Gln419Pro-SCN5A-positive relatives, each with early onset atrial arrhythmias and/or frequent, multifocal PVCs, were identified. All individuals had structurally normal hearts by echocardiography and/or cardiac magnetic resonance imaging. p.Gln419Pro-SCN5A was engineered by site directed mutagenesis and heterologously expressed in TSA201 cells. The standard whole-cell patch clamp technique was used to measure SCN5A wild-type (WT) and p.Gln419Pro-SCN5A sodium currents. Results: Analysis of the current-voltage relationship revealed that neither peak sodium current densities nor late inward sodium current were impacted by p.Gln419Pro-SCN5A. However, p.Gln419Pro-SCN5A significantly shifted V 1/2 in inactivation by -4.6 mV from -84.5±0.7 mV (WT, n=10) to -89.1±0.4 mV (Gln419Pro, n=12, p<0.05 vs. WT) and V 1/2 in activation by -11.6 mV from -30.9±1.3 mV (WT, n=10) to -42.5±1.0 mV (Gln419Pro, n=12, p<0.05 vs. WT) leading to a larger hyperpolarized window current. Flecainide dramatically reduced PVC burden in p.Gln419Pro-SCN5A-positive patients. Conclusions: p.Gln419Pro-SCN5A represents only the fifth MEPPC-causative variant described to date and the first associated with a classic MEPPC phenotype localizing outside Na v 1.5’s VSD. As class I antiarrhythmic drugs are highly efficacious in MEPPC, this clinical entity merits consideration in all young patients found to have a high burden of Purkinje-related PVCs.