2. Academic Validation
  3. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

  • Brain. 2018 Nov 1;141(11):3160-3178. doi: 10.1093/brain/awy263.
Carla Marini 1 2,  Alessandro Porro 3,  Agnès Rastetter 4,  Carine Dalle 4,  Ilaria Rivolta 5,  Daniel Bauer 6,  Renske Oegema 7,  Caroline Nava 2 4 8,  Elena Parrini 1,  Davide Mei 1,  Catherine Mercer 9,  Radhika Dhamija 10,  Chelsea Chambers 11,  Christine Coubes 12,  Julien Thévenon 13,  Paul Kuentz 13 14,  Sophie Julia 15,  Laurent Pasquier 16,  Christèle Dubourg 17,  Wilfrid Carré 17,  Anna Rosati 1,  Federico Melani 1,  Tiziana Pisano 1,  Maria Giardino 1,  A Micheil Innes 18,  Yves Alembik 19,  Sophie Scheidecker 19,  Manuela Santos 20,  Sonia Figueiroa 20,  Cristina Garrido 20,  Carlo Fusco 21,  Daniele Frattini 21,  Carlotta Spagnoli 21,  Anna Binda 5,  Tiziana Granata 22,  Francesca Ragona 22,  Elena Freri 22,  Silvana Franceschetti 22,  Laura Canafoglia 22,  Barbara Castellotti 22,  Cinzia Gellera 22,  Raffaella Milanesi 23,  Maria Margherita Mancardi 24,  Damien R Clark 25,  Fernando Kok 26,  Katherine L Helbig 27,  Shoji Ichikawa 28,  Laurie Sadler 29,  Jana Neupauerová 30,  Petra Laššuthova 30,  Katalin Šterbová 2 30,  Annick Laridon 31,  Eva Brilstra 2 7,  Bobby Koeleman 2 7,  Johannes R Lemke 2 32,  Federico Zara 33,  Pasquale Striano 2 34,  Julie Soblet 35 36 37,  Guillaume Smits 35 36 37,  Nicolas Deconinck 38,  Andrea Barbuti 23,  Dario DiFrancesco 23,  Eric LeGuern 2 4 8,  Renzo Guerrini 1 2,  Bina Santoro 39,  Kay Hamacher 6,  Gerhard Thiel 40,  Anna Moroni 3,  Jacopo C DiFrancesco 22 41,  Christel Depienne 2 4 42 43
Affiliations

Affiliations

  • 1 Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Viale Pieraccini 24, Florence, Italy.
  • 2 EuroEPINOMICS RES Consortium.
  • 3 Department of Biosciences, University of Milan, Milan, Italy.
  • 4 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
  • 5 School of Medicine and Surgery, University Milano-Bicocca, Monza, Italy.
  • 6 Computational Biology and Simulation Group, Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany.
  • 7 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 8 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, Paris, France.
  • 9 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
  • 10 Department of Clinical Genomics and Neurology, Mayo Clinic, Phoenix, AZ, USA.
  • 11 Department of Neurosciences, University of Virginia, Charlottesville, VA, USA.
  • 12 Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, Montpellier, France.
  • 13 FHU-TRANSLAD, Université de Bourgogne/CHU Dijon and INSERM UMR 1231 GAD team, Genetics of Developmental Anomalies, Université de Bourgogne-Franche Comté, Dijon, France.
  • 14 Génétique Biologique Histologie, CHRU de Besançon, Besançon, France.
  • 15 Service de génétique médicale, Pôle de biologie, CHU de Toulouse - Hôpital Purpan, Toulouse, France.
  • 16 Service de Génétique Clinique, Centre Référence Déficiences Intellectuelles de causes rares (CRDI), CHU Rennes, Rennes, France.
  • 17 Laboratoire de Génétique Moléculaire et Génomique, CHU de Rennes, Rennes, France.
  • 18 Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • 19 Laboratoires de génétique, Institut de génétique médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
  • 20 Neuropediatric Department, Centro Hospitalar do Porto, Porto, Portugal.
  • 21 Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy.
  • 22 Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • 23 Department of Biosciences, The PaceLab, Università degli Studi di Milano, Milan, Italy.
  • 24 Child Neuropsychiatry Unit, Department of Medical and Surgical Neurosciences and Rehabilitation, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • 25 Women's and Children's Hospital, Adelaide, Australia.
  • 26 Mendelics Genomic Analysis, Sao Paulo, SP, Brazil.
  • 27 Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 28 Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA, USA.
  • 29 Division of Genetics, Department of Pediatrics, Oishei Children's Hospital, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, State University of New York, Buffalo, NY, USA.
  • 30 Department of Child Neurology, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
  • 31 Department of Neurology, Academic Center for Epileptology, Kempenhaeghe/Maastricht University Medical Center, Heeze, The Netherlands.
  • 32 Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
  • 33 Laboratory of Neurogenetics and Neuroscience, Institute G Gaslini, Genova, Italy.
  • 34 Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 'G Gaslini' Institute, Genova, Italy.
  • 35 Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium.
  • 36 Department of Genetics, Hôpital Erasme ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium.
  • 37 Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles, Brussels, Belgium.
  • 38 Department of Pediatric Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, ULB, Brussels, Belgium.
  • 39 Department of Neuroscience, Columbia University, New York, NY, USA.
  • 40 Membrane Biophysics, Deparment of Biology, Technische Universität Darmstadt, Darmstadt, Germany.
  • 41 Department of Neurology, San Gerardo Hospital, University Milano-Bicocca, Monza, Italy.
  • 42 IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.
  • 43 Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
PMID: 30351409 DOI: 10.1093/brain/awy263
Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

Figures