NBEA: Developmental disease gene with early generalized epilepsy phenotypes

  • Ann Neurol. 2018 Nov;84(5):788-795. doi: 10.1002/ana.25350.
Maureen S Mulhern  1 ,  Constance Stumpel  2 ,  Nicholas Stong  1 ,  Han G Brunner  2  3 ,  Louise Bier  1 ,  Natalie Lippa  1 ,  James Riviello  4 ,  Rob P W Rouhl  5  6  7 ,  Marlies Kempers  8 ,  Rolph Pfundt  3 ,  Alexander P A Stegmann  2 ,  Mary K Kukolich  9 ,  Aida Telegrafi  10 ,  Anna Lehman  11 ,  CAUSES study ,  Elena Lopez-Rangel  11 ,  Nada Houcinat  12  13 ,  Magalie Barth  14 ,  Nicolette den Hollander  15 ,  Mariette J V Hoffer  15 ,  Sarah Weckhuysen  16  17  18 ,  EuroEPINOMICS-RES-MAE working group ,  Jolien Roovers  16  17 ,  Tania Djemie  16  17  18 ,  Diana Barca  19 ,  Berten Ceulemans  20 ,  Dana Craiu  19 ,  Johannes R Lemke  21 ,  Christian Korff  22 ,  Heather C Mefford  23 ,  Candace T Meyers  23 ,  Zsuzsanna Siegler  24 ,  Susan M Hiatt  25 ,  Gregory M Cooper  25 ,  E Martina Bebin  26 ,  Lot Snijders Blok  3  27 ,  Hermine E Veenstra-Knol  28 ,  Evan H Baugh  1 ,  Eva H Brilstra  29 ,  Catharina M L Volker-Touw  29 ,  Ellen van Binsbergen  29 ,  Anya Revah-Politi  1 ,  Elaine Pereira  30 ,  Danielle McBrian  4 ,  Mathilde Pacault  31 ,  Bertrand Isidor  31 ,  Cedric Le Caignec  31 ,  Brigitte Gilbert-Dussardier  32  33 ,  Frederic Bilan  32  33 ,  Erin L Heinzen  1  34 ,  David B Goldstein  1 ,  Servi J C Stevens  2 ,  Tristan T Sands  1  4
Affiliations
  • 1. Columbia University Medical Center, Institute for Genomic Medicine, New York, NY.
  • 2. Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
  • 3. Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 4. Department of Neurology, Columbia University Department of Neurology, New York, NY.
  • 5. Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.
  • 6. Academic Center for Epileptology, Kempenhaeghe/Maastricht University Medical Center, Maastricht, the Netherlands.
  • 7. School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
  • 8. Department of Clinical Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 9. Cook Children's Hospital, Fort Worth, TX.
  • 10. GeneDx, Gaithersburg, MD.
  • 11. Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
  • 12. University of Burgundy-Franche-Comté, UMR1231 GAD, INSERM, Dijon, France.
  • 13. Dijon Bourgogne University Hospital Center, Rare Diseases Reference Center "Developmental Anomalies and Informational Syndromes," Genetic Center, FHU-TRANSLAD, Dijon, France.
  • 14. Department of Biochemistry and Genetics, Angers University Hospital Center, Angers, France.
  • 15. Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
  • 16. Center for Molecular Neurology, VIB, Neurogenetics Group, Antwerp, Belgium.
  • 17. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 18. Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.
  • 19. Pediatric Neurology Clinic, Al Obregia Hospital, Carol Davila University of Medicine, Bucharest, Romania.
  • 20. Department of Pediatric Neurology, University Hospital Antwerp, Antwerp, Belgium.
  • 21. Institute for Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
  • 22. Pediatric Neurology Unit, Child and Adolescent Department, University Hospitals, Geneva, Switzerland.
  • 23. Department of Pediatrics, University of Washington, Seattle, WA.
  • 24. Bethesda Children's Hospital, Department of Neurology, Budapest, Hungary.
  • 25. HudsonAlpha Institute for Biotechnology, Huntsville, AL.
  • 26. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL.
  • 27. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
  • 28. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
  • 29. University Medical Center Utrecht, Department of Genetics, Utrecht, the Netherlands.
  • 30. Division of Clinical Genetics, Department of Pediatrics, New York-Presbyterian Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, NY.
  • 31. Genetics Service, Nantes University Hospital Center, Nantes, France.
  • 32. Genetics Service, Poitiers University Hospital Center, Poitiers, France.
  • 33. University of Poitiers, EA3808 NEUVACOD, Poitiers, France.
  • 34. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY.
PMID: 30269351 DOI: 10.1002/ana.25350
Abstract

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803.