Genetic analysis of hyperpolarization-activated cyclic nucleotide-gated cation channels in sudden unexpected death in epilepsy cases.

Sudden unexpected death in epilepsy (SUDEP) is the most common epilepsy-related cause of death, yet the cause is unknown. Our previous studies suggest a role for arrhythmia-related ion channel genes in the pathogenesis of SUDEP. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN1-4) channels are ion channels involved in generating spontaneous rhythmic activity in cardiac pacemaker and neuronal cells. This study sought to determine the role of pathogenic DNA variants in the HCN1-4 genes in a large SUDEP cohort collected from 1993 to 2009. Post-mortem DNA samples were amplified and analyzed for each HCN exon. Genetic analysis in 48 SUDEP cases (age range 12-82 years) identified six novel and three previously reported nonsynonymous (amino acid changing) variants in HCN1 (n = 1), HCN2 (n = 2), HCN3 (n = 2) and HCN4 (n = 4). The Phe738Cys and Pro802Ser variants in HCN2, and Gly973Arg in HCN4 were absent in control alleles and affecting highly conserved residues in the carboxyl-cytoplasmic tail region. Our results support a pathogenic link between the heart and brain in SUDEP, mediated by the HCN neuro-cardiac ion channel genes.