Somatic Mosaicism of Novel SCN5A Mutation in Purkinje System (PS) may Underlie 2:1 Block in an Infant with Long QT Syndrome (LQTS)

Somatic mosaicism is a condition that arises when DNA mutations lead to genetic variations within an individual. Recently, an infant with LQTS characterized by episodes of 2:1 block (i.e., 2 atrial/His-bundle activations for every one ventricular activation) was found to have a novel SCN5a mutation (V1762L) in ∼20% of cardiomyocytes, causing a 10-fold increase in late sodium current within affected cells. However, the mechanism by which V1762L mosaicism could give rise to this clinical phenotype remained unknown. We hypothesized that 2:1 block could arise from 20% V1762L mosaicism in the PS, regardless of its spatial distribution.To test this hypothesis, we used a biophysically-detailed 3D computational model of the ventricles and PS calibrated to approximate the size/geometry of the human neonatal heart. Versions of the model incorporating 20% V1762L mosaicism with diffuse or clustered distributions in the ventricles and PS were generated using a stochastic approach. To examine the arrhythmogenic propensity of the heart models, simulated normal sinus rhythm (coupling interval, CI=400ms) was interrupted by two consecutive abnormally timed stimuli (variable CIs: 300-700ms in 50ms intervals).Ventricular mosaicism alone did not lead to 2:1 block. However, once mosaicism was incorporated into the PS, a majority of all pacing sequences in each model (diffuse: 79%, clustered: 80%) resulted in 2:1 block. Even pacing sequences with CIs within the physiological range for infant heart rates (CI=400-600ms) resulted in 2:1 block (diffuse: 48%, clustered: 52%). Left bundle branch block, a highly arrhythmogenic activation pattern, was also observed (diffuse: 4%, clustered: 2%).We demonstrated a possible link between cell-scale phenotypic variability and organ-scale arrhythmogenesis by showing that 20% V1762L mosaicism in the PS, regardless of spatial distribution, can result in 2:1 block.