The majority of HCN1 variants known to be pathogenic are single nucleotide substitutions that lead to the replacement of one amino acid by another one in the protein (missense variants). The severity of the epilepsy and intellectual disability depends on where the variant is located in the channel and the nature of the change. Mutations in transmembrane domains or domains forming a crucial part of the channel are usually associated with more severe phenotypes than mutations located in regulatory parts of the protein.
The precise mechanisms by which the mutations lead to epilepsy is not completely understood. Many HCN1 mutations studied have a strong effect on the channel: some completely alter its function while others lead to a channel that activates more rapidly or with different kinetics. Mutations that lead to the loss of channel activity are thought to have a negative effect on the channel expressed by the chromosome which does not carry any variant (dominant negative effect).
As HCN1– epilepsy resembles other types of genetic epilepsies, the diagnosis relies on the identification of a HCN1 mutation. This can be done by sequencing HCN1, alone or together with other genes involved in epilepsy, or by sequencing all the regions of the genome coding for proteins (exome). Additional studies can be necessary to prove the pathogenic nature of the variant identified if this variant has not been identified in another family before.