While HCN4 channelopathies have been mostly associated so far with a variety of different types of inheritable cardiac arrhythmias, the data presented here show that dysfunctional HCN4 channels can also be involved in human epileptogenesis, demonstrating for the first time that a loss-of-function HCN4 mutation can lead to increased neuronal excitability. Here, HCN4 is linked to cardiac rhythm disease.