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
  • 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: [email protected].
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.