The association between HCN4 dysfunction and cardiac arrhythmias was initially suggested by the identification of a splicing mutation in a suspected Brugada syndrome (BrS) patient (Ueda et al., 2009), with computational modeling indicating that the HCN4-mediated If current (characterized by mixed Na+/K+ permeability and incomplete deactivation) contributes to ventricular repolarization and may predispose to bradycardia-associated arrhythmias [58]. This evidence concerns the gene HCN4 and cardiac rhythm disease.