GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.

Authors

Platzer K1, Yuan H2,3, Schütz H4, Winschel A4, Chen W2, Hu C2, Kusumoto H2, Heyne HO1, Helbig KL5, Tang S5, Willing MC6, Tinkle BT7, Adams DJ8, Depienne C9,10,11,12, Keren B9,10, Mignot C10, Frengen E13, Strømme P14, Biskup S15, Döcker D15, Strom TM16, Mefford HC17, Myers CT17, Muir AM17, LaCroix A17, Sadleir L18, Scheffer IE19, Brilstra E20, van Haelst MM20, van der Smagt JJ20, Bok LA21, Møller RS22,23, Jensen UB24, Millichap JJ25, Berg AT25, Goldberg EM26,27, De Bie I28, Fox S28, Major P29, Jones JR30, Zackai EH31, Abou Jamra R1,32, Rolfs A32, Leventer RJ33,34, Lawson JA35, Roscioli T36, Jansen FE37, Ranza E38, Korff CM39, Lehesjoki AE40,41, Courage C40,41, Linnankivi T42, Smith DR43, Stanley C43, Mintz M44, McKnight D45, Decker A45, Tan WH46, Tarnopolsky MA47, Brady LI47, Wolff M48, Dondit L49, Pedro HF50, Parisotto SE50, Jones KL51, Patel AD52,53, Franz DN54, Vanzo R55, Marco E56, Ranells JD57, Di Donato N58, Dobyns WB59,60,61, Laube B4, Traynelis SF2,3, Lemke JR1.

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  1. Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
  2. Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia, USA.
  3. Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, Georgia, USA.
  4. Department of Neurophysiology and Neurosensory Systems, Technical University Darmstadt, Darmstadt, Hessen, Germany.
  5. Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
  6. Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
  7. Advocate Children’s Hospital, Park Ridge, Illinois, USA.
  8. Genetics and Metabolism, Goryeb Children’s Hospital, Atlantic Health System, Morristown, New Jersey, USA.
  9. INSERM, U 1127, Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR 7225, Institut du cerveau et de la moelle épinière (ICM), Paris, France.
  10. Département de Génétique, Centre de Référence des Déficiences Intellectuelles de Causes Rares, GRC UPMC “Déficiences Intellectuelles et Autisme”, Hôpital de la Pitié-Salpêtrière, Paris, France.
  11. UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.
  12. Laboratoire de cytogénétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
  13. Department of Medical Genetics, Oslo University Hospitals and University of Oslo, Oslo, Norway.
  14. Department of Pediatrics, Oslo University Hospitals and University of Oslo, Oslo, Norway.
  15. Practice for Human Genetics and CeGaT GmbH, Tübingen, Germany.
  16. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  17. Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.
  18. Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
  19. Department of Medicine, University of Melbourne, Austin Health and Royal Children’s Hospital, Melbourne, Victoria, Australia.
  20. Department of Genetics, Utrecht University Medical Center, Utrecht, The Netherlands.
  21. Department of Paediatrics, Màxima Medical Centre, Veldhoven, The Netherlands.
  22. The Danish Epilepsy Centre Filadelfia, Dianalund, Denmark.
  23. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
  24. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
  25. Departments of Pediatrics, Epilepsy Center and Division of Neurology Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  26. Division of Neurology, The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  27. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  28. Department of Medical Genetics, Montreal Children’s Hospital, McGill University Health Center, Montreal, Canada.
  29. Department of Neurological Sciences, Université de Montréal, CHU Ste-Justine, Montreal, Canada.
  30. Greenwood Genetic Center, Greenwood, South Carolina, USA.
  31. Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  32. Centogene AG, Rostock, Germany.
  33. Department of Neurology, Royal Children’s Hospital, Melbourne, Victoria, Australia.
  34. Murdoch Childrens Research Institute and Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.
  35. Department of Neurology, Sydney Children’s Hospital, Sydney, New South Wales, Australia.
  36. Genome.One, Sydney, New South Wales, Australia.
  37. Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands.
  38. Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
  39. Department of Child and Adolescent, Neurology Unit, University Hospitals of Geneva, Geneva, Switzerland.
  40. The Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.
  41. Research Programs Unit, Molecular Neurology and Neuroscience Center, University of Helsinki, Helsinki, Finland.
  42. Department of Pediatric Neurology, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  43. Courtagen Life Sciences, Woburn, Massachusetts, USA.
  44. The Center for Neurological and Neurodevelopmental Health and the Clinical Research Center of New Jersey, Voorhees, New Jersey, USA.
  45. GeneDx, Gaithersburg, Maryland, USA.
  46. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts, USA.
  47. Department of Pediatrics, McMaster University Children’s Hospital, Hamilton, Ontario, Canada.
  48. Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tubingen, Germany.
  49. Department of Pediatric Neurology and Center for Developmental Medicine, Olgahospital Stuttgart, Stuttgart, Germany.
  50. Hackensack University Medical Center, Hackensack, New Jersey, USA.
  51. Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
  52. Nationwide Children’s Hospital, Columbus, Ohio, USA.
  53. The Ohio State University College of Medicine, Columbus, Ohio, USA.
  54. Department of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
  55. Lineagen, Inc., Salt Lake City, Utah, USA.
  56. Department of Neurology, University of San Francisco School of Medicine, San Francisco, California, USA.
  57. Department of Pediatrics, University of South Florida, Tampa, Florida, USA.
  58. Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany.
  59. Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA.
  60. Department of Pediatrics, University of Washington, Seattle, Washington, USA.
  61. Department of Neurology, University of Washington, Seattle, Washington, USA.

Abstract

BACKGROUND:

We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine.

METHODS:

Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.

RESULTS:

Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.

CONCLUSIONS:

In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.