2. Academic Validation
  3. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

  • Am J Hum Genet. 2018 Nov 1;103(5):666-678. doi: 10.1016/j.ajhg.2018.09.006.
Katherine L Helbig 1,  Robert J Lauerer 2,  Jacqueline C Bahr 2,  Ivana A Souza 3,  Candace T Myers 4,  Betül Uysal 2,  Niklas Schwarz 2,  Maria A Gandini 3,  Sun Huang 3,  Boris Keren 5,  Cyril Mignot 5,  Alexandra Afenjar 6,  Thierry Billette de Villemeur 7,  Delphine Héron 5,  Caroline Nava 5,  Stéphanie Valence 5,  Julien Buratti 5,  Christina R Fagerberg 8,  Kristina P Soerensen 9,  Maria Kibaek 9,  Erik-Jan Kamsteeg 10,  David A Koolen 10,  Boudewijn Gunning 11,  H Jurgen Schelhaas 12,  Michael C Kruer 13,  Jordana Fox 13,  Somayeh Bakhtiari 13,  Randa Jarrar 13,  Sergio Padilla-Lopez 13,  Kristin Lindstrom 14,  Sheng Chih Jin 15,  Xue Zeng 15,  Kaya Bilguvar 15,  Antigone Papavasileiou 16,  Qinghe Xing 17,  Changlian Zhu 18,  Katja Boysen 19,  Filippo Vairo 20,  Brendan C Lanpher 20,  Eric W Klee 20,  Jan-Mendelt Tillema 20,  Eric T Payne 21,  Margot A Cousin 22,  Teresa M Kruisselbrink 23,  Myra J Wick 23,  Joshua Baker 24,  Eric Haan 25,  Nicholas Smith 26,  Azita Sadeghpour 27,  Erica E Davis 27,  Nicholas Katsanis 27,  Task Force for Neonatal Genomics,  Mark A Corbett 28,  Alastair H MacLennan 28,  Jozef Gecz 28,  Saskia Biskup 29,  Eva Goldmann 30,  Lance H Rodan 31,  Elizabeth Kichula 1,  Eric Segal 32,  Kelly E Jackson 33,  Alexander Asamoah 33,  David Dimmock 34,  Julie McCarrier 34,  Lorenzo D Botto 35,  Francis Filloux 36,  Tatiana Tvrdik 37,  Gregory D Cascino 21,  Sherry Klingerman 21,  Catherine Neumann 38,  Raymond Wang 39,  Jessie C Jacobsen 40,  Melinda A Nolan 41,  Russell G Snell 40,  Klaus Lehnert 40,  Lynette G Sadleir 42,  Britt-Marie Anderlid 43,  Malin Kvarnung 44,  Renzo Guerrini 45,  Michael J Friez 46,  Michael J Lyons 46,  Jennifer Leonhard 47,  Gabriel Kringlen 48,  Kari Casas 48,  Christelle M El Achkar 49,  Lacey A Smith 50,  Alexander Rotenberg 51,  Annapurna Poduri 49,  Alba Sanchis-Juan 52,  Keren J Carss 52,  Julia Rankin 53,  Adam Zeman 54,  F Lucy Raymond 55,  Moira Blyth 56,  Bronwyn Kerr 57,  Karla Ruiz 58,  Jill Urquhart 59,  Imelda Hughes 58,  Siddharth Banka 57,  Deciphering Developmental Disorders Study 60,  Ulrike B S Hedrich 2,  Ingrid E Scheffer 61,  Ingo Helbig 62,  Gerald W Zamponi 3,  Holger Lerche 2,  Heather C Mefford 63
Affiliations

Affiliations

  • 1 Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 2 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
  • 3 Department of Physiology & Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada.
  • 4 Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
  • 5 APHP, Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière et GHUEP Hôpital Trousseau; Sorbonne Université, GRC "Déficience Intellectuelle et Autisme," 75013 Paris, France.
  • 6 Sorbonne Université, GRC n°19, Pathologies Congénitales du Cervelet-LeucoDystrophies, Département de Génétique et Embryologie Médicale, AP-HP, Hôpital d'Enfants Armand Trousseau, Centre de Référence des Déficits Intellectuels de Causes Rares, 75012 Paris, France.
  • 7 Sorbonne Université, GRC n°19, Pathologies Congénitales du Cervelet-LeucoDystrophies, Service de Neuropédiatrie, AP-HP, Hôpital d'Enfants Armand Trousseau; Centre de Référence des Déficits Intellectuels de Causes Rares; Inserm U 1141, 75012 Paris, France.
  • 8 Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark; H.C. Andersen Children's Hospital, Odense University Hospital, 5000 Odense, Denmark.
  • 9 Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.
  • 10 Department of Human Genetics, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
  • 11 Stichting Epilepsie Instellingen Nederland, 8025 Zwolle, the Netherlands.
  • 12 Department of Neurology, Academic Center for Epileptology, Kempenhaeghe and Maastricht UMC, 5591 Heeze, the Netherlands.
  • 13 Barrow Neurological Institute, Phoenix Children's Hospital, Departments of Child Health, Genetics, Neurology, and Cellular & Molecular Medicine, University of Arizona College of Medicine, Phoenix, AZ 85013, USA.
  • 14 Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
  • 15 Yale School of Medicine, New Haven, CT 06510, USA.
  • 16 Department of Pediatric Neurology, Penteli Children's Hospital, 152 36 Athens, Greece.
  • 17 Institute of Biomedical Science and Children's Hospital Fudan University, 201102 Shanghai, China.
  • 18 Perinatal Center, Sahlgrenska Academy, Gothenburg University, 413 46 Gothenburg, Sweden; Hospital of Zhengzhou University, 450001 Zhengzhou, China.
  • 19 Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
  • 20 Department of Health Science Research, Mayo Clinic, Rochester, MN 55905, USA.
  • 21 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 22 Department of Health Science Research, Mayo Clinic, Rochester, MN 55905, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • 23 Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
  • 24 University of Illinois Chicago College of Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
  • 25 Adult Genetics Unit, Royal Adelaide Hospital, and School of Medicine, University of Adelaide, Adelaide, SA 5000, Australia.
  • 26 Department of Neurology, Women's and Children's Hospital, University of Adelaide, North Adelaide, SA 5006, Australia.
  • 27 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
  • 28 Adelaide Medical School, Robinson Research Institute, University of Adelaide, North Adelaide, SA 5006, Australia.
  • 29 CeGaT, 72076 Tübingen, Germany.
  • 30 Department of Human Genetics, University of Tübingen, 72076 Tübingen, Germany.
  • 31 Division of Genetics and Genomics and Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA.
  • 32 Northeast Regional Epilepsy Group, Hackensack University Medical Center, Hackensack, NJ 07601, USA.
  • 33 University of Louisville, Louisville, KY 40292, USA.
  • 34 Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
  • 35 Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84113, USA.
  • 36 Division of Pediatric Neurology, Departments of Pediatrics and Neurology, University of Utah, Salt Lake City, UT 84113, USA.
  • 37 ARUP Laboratories, Salt Lake City, UT 84108, USA.
  • 38 Division of Metabolic Disorders CHOC Children's Hospital, Orange, CA 92868, USA.
  • 39 Division of Metabolic Disorders CHOC Children's Hospital, Orange, CA 92868, USA; Department of Pediatrics, University of California-Irvine School of Medicine, Irvine, CA 92617, USA.
  • 40 Centre for Brain Research and School of Biological Sciences, The University of Auckland, Auckland 1142, New Zealand.
  • 41 Department of Neurology, Starship Children's Health, Auckland 1023, New Zealand.
  • 42 Department of Paediatrics and Child Health, University of Otago Wellington, Wellington South 6242, New Zealand.
  • 43 Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden.
  • 44 Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden.
  • 45 Department of Neuroscience, Azienda Ospedaliero-Universitaria Meyer, University of Florence, 50139 Florence, Italy.
  • 46 Greenwood Genetic Center, Greenwood, SC 29646, USA.
  • 47 Medical Genetics, Sanford Health, Bemidji, MN 56601, USA.
  • 48 Medical Genetics, Sanford Health, Fargo, ND 58102, USA.
  • 49 Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02215, USA.
  • 50 Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 51 Department of Neurology, Harvard Medical School, Boston, MA 02215, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 52 Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0QQ, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • 53 Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
  • 54 Department of Neurology, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
  • 55 NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
  • 56 Yorkshire Regional Genetics Service, Chapel Allerton Hospital Leeds Teaching Hospitals NHS Trust, Leeds LS7 4SA, UK.
  • 57 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University Foundation NHS Trust, Health Innovation, Manchester M13 9WL, UK.
  • 58 Department of Paediatric Neurology, Royal Manchester Children's Hospital, Manchester University Foundation NHS Trust, Health Innovation, Manchester M13 9WL, UK.
  • 59 Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University Foundation NHS Trust, Health Innovation, Manchester M13 9WL, UK.
  • 60 Wellcome Sanger Institute, Cambridge CB10 1SA, UK.
  • 61 Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia; The Florey Institute and Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Neurology, Royal Children's Hospital, Parkville, VIC 3052, Australia.
  • 62 Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neuropediatrics, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
  • 63 Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: hmefford@uw.edu.
PMID: 30343943 DOI: 10.1016/j.ajhg.2018.09.006
Abstract

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CAV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation Sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CAV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Keywords

CACNA1E, ion channel; arthrogryposis; calcium channel; epilepsy.

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