Authorship

The genetic architecture of common epilepsies is largely unknown. HCNs are excellent epilepsy candidate genes because of their fundamental neurophysiological roles. Screening in subjects with febrile seizures and genetic epilepsy with febrile seizures plus revealed that 2.4 % carried a common triple proline deletion (delPPP) in HCN2 that was seen in only 0.2 % of blood bank controls. Currents generated by mutant HCN2 channels were ~35 % larger than those of controls; an effect revealed using automated electrophysiology and an appropriately powered sample size. This is the first association of HCN2 and familial epilepsy, demonstrating gain of function of HCN2 current as a potential contributor to polygenic epilepsy. Febrile seizures (FS) and idiopathic generalized epilepsy (IGE), including genetic epilepsy with febrile seizures plus (GEFS+), are common epilepsy syndromes that show complex inheritance, where a combination of susceptibility variants is proposed to underlie the etiology in most cases.1-3 A small number of susceptibility genes for IGE have bee