Phenotypic overlap of cardiac sodium channelopathies: individual-specific or mutation-specific?

Mutations in the cardiac sodium channel gene SCN5A are responsible for a spectrum of hereditary arrhythmias, including type-3 long QT syndrome (LQT3), Brugada syndrome (BrS), conduction disturbance and sinus node dysfunction. These syndromes were originally regarded as independent entities with distinct clinical manifestations and biophysical properties, but recent evidence shows considerable clinical overlap, implying a new disease entity known as an overlap syndrome of cardiac sodium channelopathy. Class IC sodium-channel blockers often induced the BrS phenotype in some patients with LQT3, confirming the clinical overlap of LQT3 and BrS. It also raises a concern about the safety of the class IC drug and questions about the determinants of overlap. Here, an overview is given of current knowledge on the clinical features, prevalence, and molecular and biophysical mechanisms underlying overlap syndrome to gain more insight into this complex issue and generate better therapeutic strategies for patient management.