HCN1 (hyperpolarization-activated, cyclic nucleotide-gated channel 1) encodes one of four subunits forming homo- and heterotetrameric voltage-gated ion channels activated by hyperpolarization and potentiated by binding of cAMP. HCN1 is the main subunit expressed postnatally in the human cortex and has an important function in the control of neuronal excitability.
Clinical features
HCN1-related disorders have variable clinical manifestations including polymorphic seizures with predominant phenotypes expanding from genetic generalized epilepsy (GGE) or genetic generalized epilepsy with febrile seizure plus (GEFS+) to neonatal/infantile onset otherwise unclassified developmental epileptic encephalopathy (DEE). Mild to severe intellectual disability is observed in most patients.
Prevalence
The exact prevalence is not yet known but it is a rare disorder, with less than 50 patients reported so far.
Inheritance
HCN1-related disorders follow autosomal dominant inheritance. Mutations causing severe sporadic disorders usually occur de novo while mutations associated with milder epilepsies segregate within families, sometimes with incomplete penetrance.