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Genotype-phenotype correlations
Original Article
GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects
  1. Konrad Platzer1,
  2. Hongjie Yuan2,3,
  3. Hannah Schütz4,
  4. Alexander Winschel4,
  5. Wenjuan Chen2,
  6. Chun Hu2,
  7. Hirofumi Kusumoto2,
  8. Henrike O Heyne1,
  9. Katherine L Helbig5,
  10. Sha Tang5,
  11. Marcia C Willing6,
  12. Brad T Tinkle7,
  13. Darius J Adams8,
  14. Christel Depienne9,10,11,12,
  15. Boris Keren9,10,
  16. Cyril Mignot10,
  17. Eirik Frengen13,
  18. Petter Strømme14,
  19. Saskia Biskup15,
  20. Dennis Döcker15,
  21. Tim M Strom16,
  22. Heather C Mefford17,
  23. Candace T Myers17,
  24. Alison M Muir17,
  25. Amy LaCroix17,
  26. Lynette Sadleir18,
  27. Ingrid E Scheffer19,
  28. Eva Brilstra20,
  29. Mieke M van Haelst20,
  30. Jasper J van der Smagt20,
  31. Levinus A Bok21,
  32. Rikke S Møller22,23,
  33. Uffe B Jensen24,
  34. John J Millichap25,
  35. Anne T Berg25,
  36. Ethan M Goldberg26,27,
  37. Isabelle De Bie28,
  38. Stephanie Fox28,
  39. Philippe Major29,
  40. Julie R Jones30,
  41. Elaine H Zackai31,
  42. Rami Abou Jamra1,32,
  43. Arndt Rolfs32,
  44. Richard J Leventer33,34,
  45. John A Lawson35,
  46. Tony Roscioli36,
  47. Floor E Jansen37,
  48. Emmanuelle Ranza38,
  49. Christian M Korff39,
  50. Anna-Elina Lehesjoki40,41,
  51. Carolina Courage40,41,
  52. Tarja Linnankivi42,
  53. Douglas R Smith43,
  54. Christine Stanley43,
  55. Mark Mintz44,
  56. Dianalee McKnight45,
  57. Amy Decker45,
  58. Wen-Hann Tan46,
  59. Mark A Tarnopolsky47,
  60. Lauren I Brady47,
  61. Markus Wolff48,
  62. Lutz Dondit49,
  63. Helio F Pedro50,
  64. Sarah E Parisotto50,
  65. Kelly L Jones51,
  66. Anup D Patel52,53,
  67. David N Franz54,
  68. Rena Vanzo55,
  69. Elysa Marco56,
  70. Judith D Ranells57,
  71. Nataliya Di Donato58,
  72. William B Dobyns59,60,61,
  73. Bodo Laube4,
  74. Stephen F Traynelis2,3,
  75. Johannes R Lemke1
  1. 1 Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany
  2. 2 Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia, USA
  3. 3 Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, Georgia, USA
  4. 4 Department of Neurophysiology and Neurosensory Systems, Technical University Darmstadt, Darmstadt, Hessen, Germany
  5. 5 Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA
  6. 6 Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
  7. 7 Advocate Children’s Hospital, Park Ridge, Illinois, USA
  8. 8 Genetics and Metabolism, Goryeb Children’s Hospital, Atlantic Health System, Morristown, New Jersey, USA
  9. 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. 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. 11 UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France
  12. 12 Laboratoire de cytogénétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  13. 13 Department of Medical Genetics, Oslo University Hospitals and University of Oslo, Oslo, Norway
  14. 14 Department of Pediatrics, Oslo University Hospitals and University of Oslo, Oslo, Norway
  15. 15 Practice for Human Genetics and CeGaT GmbH, Tübingen, Germany
  16. 16 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  17. 17 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, USA
  18. 18 Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
  19. 19 Department of Medicine, University of Melbourne, Austin Health and Royal Children’s Hospital, Melbourne, Victoria, Australia
  20. 20 Department of Genetics, Utrecht University Medical Center, Utrecht, The Netherlands
  21. 21 Department of Paediatrics, Màxima Medical Centre, Veldhoven, The Netherlands
  22. 22 The Danish Epilepsy Centre Filadelfia, Dianalund, Denmark
  23. 23 Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
  24. 24 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
  25. 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. 26 Division of Neurology, The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  27. 27 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  28. 28 Department of Medical Genetics, Montreal Children’s Hospital, McGill University Health Center, Montreal, Canada
  29. 29 Department of Neurological Sciences, Université de Montréal, CHU Ste-Justine, Montreal, Canada
  30. 30 Greenwood Genetic Center, Greenwood, South Carolina, USA
  31. 31 Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  32. 32 Centogene AG, Rostock, Germany
  33. 33 Department of Neurology, Royal Children’s Hospital, Melbourne, Victoria, Australia
  34. 34 Murdoch Childrens Research Institute and Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia
  35. 35 Department of Neurology, Sydney Children’s Hospital, Sydney, New South Wales, Australia
  36. 36 Genome.One, Sydney, New South Wales, Australia
  37. 37 Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands
  38. 38 Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
  39. 39 Department of Child and Adolescent, Neurology Unit, University Hospitals of Geneva, Geneva, Switzerland
  40. 40 The Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland
  41. 41 Research Programs Unit, Molecular Neurology and Neuroscience Center, University of Helsinki, Helsinki, Finland
  42. 42 Department of Pediatric Neurology, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  43. 43 Courtagen Life Sciences, Woburn, Massachusetts, USA
  44. 44 The Center for Neurological and Neurodevelopmental Health and the Clinical Research Center of New Jersey, Voorhees, New Jersey, USA
  45. 45 GeneDx, Gaithersburg, Maryland, USA
  46. 46 Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts, USA
  47. 47 Department of Pediatrics, McMaster University Children’s Hospital, Hamilton, Ontario, Canada
  48. 48 Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tubingen, Germany
  49. 49 Department of Pediatric Neurology and Center for Developmental Medicine, Olgahospital Stuttgart, Stuttgart, Germany
  50. 50 Hackensack University Medical Center, Hackensack, New Jersey, USA
  51. 51 Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi, USA
  52. 52 Nationwide Children’s Hospital, Columbus, Ohio, USA
  53. 53 The Ohio State University College of Medicine, Columbus, Ohio, USA
  54. 54 Department of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  55. 55 Lineagen, Inc., Salt Lake City, Utah, USA
  56. 56 Department of Neurology, University of San Francisco School of Medicine, San Francisco, California, USA
  57. 57 Department of Pediatrics, University of South Florida, Tampa, Florida, USA
  58. 58 Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany
  59. 59 Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA
  60. 60 Department of Pediatrics, University of Washington, Seattle, Washington, USA
  61. 61 Department of Neurology, University of Washington, Seattle, Washington, USA
  1. Correspondence to Dr Johannes R Lemke, Institute of Human Genetics, University of Leipzig, Leipzig, Germany; johannes.lemke{at}medizin.uni-leipzig.de

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.

  • epileptic encephalopathy
  • pathogenic GRIN2B mutations
  • channelopathy
  • clustering of missense variants
  • precision medicine

https://doi.org/10.1136/jmedgenet-2016-104509

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    Footnotes

    • Contributors KP, HOY, BIL, SFT, JRL conceived the project. KP, KLH, ST, MCW, BTT, DJA, CD, BK, CM, EF, SB, DD, TMS, HCM, CTM, AMM, AL, LS, IES, EB, LAB, RSM, UBJ, JJM, ATB, EMG, IDB, SF, PM, JRJ, EHZ, RAJ, AR, RJL, JL, TR, FEJ, ER, CMK, MMvH, JJvdS, AEL, CC, TL, DRS, CS, MM, DM, AD, WHT, MAT, BIL, MW, LD, SEP, KLJ, ADP, DNF, RV, EM, JDR, ND, WBD, SFT, JRL recruited and phenotyped patients. HY, HS, AW, WC, CH, HK, BIL, SFT performed in vitro experiments. KP, HY, HS, AW, WC, CH, HK, HOH, ND, WBD, BL, SFT, JRL performed data analysis and statistics. KP, HY, SFT, JRL wrote the manuscript. All authors edited the manuscript.

    • Funding Funding for the project was provided by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R01HD082373 to HY), by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454 (to HY), and by the National Institute of Neurological Disorders and Stroke (NS036654, R01NS065371 and R24NS092989 to SFT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

      Additional funding was received from the Australian NHMRC (512123 to TR), NIH NINDS training grant (K12 NS049453 to EMG), Cure Kids NZ to LS and the SNSF Early Postdoc fellowship (P2SKP3_164945 to CC).

      Funding for the DECIPHER project was provided by the Wellcome Trust.

    • Competing interests SFT is a consultant of Janssen Pharmaceuticals, Inc., Pfizer Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, and co-founder of NeurOp Inc.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from and via email from decipher@sanger.ac.uk.