Title: De novo mutations in HCN1 cause early infantile epileptic encephalopathy.

Authors: Caroline Nava, Carine Dalle, Agnès Rastetter, Pasquale Striano, Carolien G F de Kovel, Rima Nabbout, Claude Cancès, Dorothee Ville, Eva H Brilstra, Giuseppe Gobbi, Emmanuel Raffo, Delphine Bouteiller, Yannick Marie, Oriane Trouillard, Angela Robbiano, Boris Keren, Dahbia Agher, Emmanuel Roze, Suzanne Lesage, Aude Nicolas, Alexis Brice, Michel Baulac, Cornelia Vogt, Nady El Hajj, Eberhard Schneider, Arvid Suls, Sarah Weckhuysen, Padhraig Gormley, Anna-Elina Lehesjoki, Peter De Jonghe, Ingo Helbig, Stéphanie Baulac, Federico Zara, Bobby P C Koeleman, , Thomas Haaf, Eric LeGuern, Christel Depienne

Journal, date & volume: Nat. Genet., 2014 Jun , 46, 640-5

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24747641

Abstract
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to cationic Ih current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch-clamp recordings of Ih currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.