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

Authors

Helbig KL1, Lauerer RJ2, Bahr JC2, Souza IA3, Myers CT4, Uysal B2, Schwarz N2, Gandini MA3, Huang S3, Keren B5, Mignot C5, Afenjar A6, Billette de Villemeur T7, Héron D5, Nava C5, Valence S5, Buratti J5, Fagerberg CR8, Soerensen KP9, Kibaek M9, Kamsteeg EJ10, Koolen DA10, Gunning B11, Schelhaas HJ12, Kruer MC13, Fox J13, Bakhtiari S13, Jarrar R13, Padilla-Lopez S13, Lindstrom K14, Jin SC15, Zeng X15, Bilguvar K15, Papavasileiou A16, Xin Q17, Zhu C18, Boysen K19, Vairo F20, Lanpher BC20, Klee EW20, Tillema JM20, Payne ET21, Cousin MA22, Kruisselbrink TM23, Wick MJ23, Baker J24, Haan E25, Smith N26, Corbett MA27, MacLennan AH27, Gecz J27, Biskup S28, Goldmann E29, Rodan LH30, Kichula E1, Segal E31, Jackson KE32, Asamoah A32, Dimmock D33, McCarrier J33, Botto LD34, Filloux F35, Tvrdik T36, Cascino GD21, Klingerman S21, Neumann C37, Wang R38, Jacobsen JC39, Nolan MA40, Snell RG39, Lehnert K39, Sadleir LG41, Anderlid BM42, Kvarnung M43, Guerrini R44, Friez MJ45, Lyons MJ45, Leonhard J46, Kringlen G47, Casas K47, El Achkar CM48, Smith LA49, Rotenberg A50, Poduri A48, Sanchis-Juan A51, Carss KJ51, Rankin J52, Zeman A53, Raymond FL54, Blyth M55, Kerr B56, Ruiz K57, Urquhart J58, Hughes I57, Banka S56; Deciphering Developmental Disorders Study59, Hedrich UBS2, Scheffer IE60, Helbig I61, Zamponi GW3, Lerche H2, Mefford HC62.
  1. Division of Neurology, Children`s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  2. Department of Neurology and Epileptology, Hertie Insitute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
  3. Department of Physiology & Pharmacology, Hotchkiss Brain Insitute and Alberta Children’s Hospital Research Insitute, 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 Insitute, Phoenix Children’s Hospital, Departments of Child Health, Genetics, Neurology, and Cellular & Molecular Medicine, University of Arizona College of Medicine, Phoenix, AZ 85016, USA.
  14. Division of Genetics and Metabolism, Phoenix Children’s Hospital, 152 36 Athens, Greece.
  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. Adelaide Medical School, Robinson Research Institute, University of Adelaide, North Adelaide, SA 5006, Australia.
  28. CeGaT, 72076 Tübingen, Germany.
  29. Department of Human Genetics, University of Tübingen, 72076 Tübingen, Germany.
  30. 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.
  31. Northeast Regional Epilepsy Group, Hackensack University Medical Center, Hackensack, NJ 07601, USA.
  32. University of Louisville, Louisville, KY 40292, USA.
  33. Children’s Hospital of Wisconsin, Milwaukee, WI 53226, USA.
  34. Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84113, USA.
  35. Division of Pediatric Neurology, Departments of Pediatrics and Neurology, University of Utah, Salt Lake City, UT 84113, USA.
  36. ARUP Laboratories, Salt Lake City, UT 84108, USA.
  37. Division of Metabolic Disorders CHOC Children’s Hospital, Orange, CA 92868, USA.
  38. 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.
  39. Centre for Brain Research and School of Biological Sciences, The University of Auckland, Auckland 1142, New Zealand.
  40. Department of Neurology, Starship Children’s Health, Auckland 1023, New Zealand.
  41. Department of Paediatrics and Child Health, University of Otago Wellington, Wellington South 6242, New Zealand.
  42. Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden.
  43. Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden.
  44. Department of Neuroscience, Azienda Ospedaliero-Universitaria Meyer, University of Florence, 50139 Florence, Italy.
  45. Greenwood Genetic Center, Greenwood, SC 29646, USA.
  46. Medical Genetics, Sanford Health, Bemidji, MN 56601, USA.
  47. Medical Genetics, Sanford Health, Fargo, ND 58102, USA.
  48. Epilepsy Genetics Program, Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02215, USA.
  49. Epilepsy Genetics Program, Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, USA.
  50. Department of Neurology, Harvard Medical School, Boston, MA 02215, USA; Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, USA.
  51. 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.
  52. Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
  53. Department of Neurology, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
  54. 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.
  55. Yorkshire Regional Genetics Service, Chapel Allerton Hospital Leeds Teaching Hospitals NHS Trust, Leeds LS7 4SA, UK.
  56. 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.
  57. Department of Paediatric Neurology, Royal Manchester Children’s Hospital, Manchester University Foundation NHS Trust, Health Innovation, Manchester M13 9WL, UK.
  58. Manchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester University Foundation NHS Trust, Health Innovation, Manchester M13 9WL, UK.
  59. Wellcome Sanger Institute, Cambridge CB10 1SA, UK.
  60. 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.
  61. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neuropediatrics, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
  62. Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: hmefford@uw.edu.

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.