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Genotype-phenotype correlations
Original research
Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B
  1. Stefanie Brock1,2,
  2. Annie Laquerriere3,4,
  3. Florent Marguet3,4,
  4. Scott J Myers5,6,
  5. Yuan Hongjie5,6,
  6. Diana Baralle7,
  7. Tim Vanderhasselt8,
  8. Katrien Stouffs2,9,
  9. Kathelijn Keymolen9,
  10. Sukhan Kim5,6,
  11. James Allen5,6,
  12. Gil Shaulsky5,6,
  13. Jamel Chelly10,11,
  14. Pascale Marcorelle12,
  15. Jacqueline Aziza13,
  16. Laurent Villard14,15,
  17. Elise Sacaze16,
  18. Marie C Y de Wit17,
  19. Martina Wilke18,
  20. Grazia Maria Simonetta Mancini18,
  21. Ute Hehr19,
  22. Derek Lim20,
  23. Sahar Mansour21,
  24. Stephen F Traynelis5,6,
  25. Claire Beneteau22,23,
  26. Marie Denis-Musquer23,24,
  27. Anna C Jansen25,
  28. Andrew E Fry26,27,
  29. Nadia Bahi-Buisson28,29
  1. 1 Department of Pathology, Universitair Ziekenhuis Brussel, Brussels, Belgium
  2. 2 Neurogenetics Research Group, Reproduction Genetics and Regenerative Medicine Research Cluster, Vrije Universiteit Brussel, Brussels, Belgium
  3. 3 Normandy Centre for Genomic and Personalized Medicine, INSERM U1245, Rouen, France
  4. 4 Department of Pathology, Rouen University Hospital, Rouen, France
  5. 5 Department of Pharmacology and Chemical Biology, Emory University School of Medicine Atlanta, Atlanta, Georgia, USA
  6. 6 Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine Atlanta, Atlanta, Georgia, USA
  7. 7 Human Development and Health, University of Southampton, Southampton, UK
  8. 8 Department of Radiology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
  9. 9 Center for Reproduction and Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
  10. 10 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U1258, Université de Strasbourg, Strasbourg, France
  11. 11 Laboratoire de Diagnostic Génétique, Hôpitaux Universitaire de Strasbourg, Strasbourg, France
  12. 12 Service d'Anatomie Pathologique, Centre Hospitalier Universitaire de Brest; Laboratoire Neurosciences de Brest, Université de Brest, Brest, France
  13. 13 Department of Pathology, University Institute for Cancer, Toulouse, France
  14. 14 Inserm, Marseille Medical Genetics Center, Aix-Marseille University, Marseille, France
  15. 15 Department of Medical Genetics, La Timone Children's Hospital, Marseille, France
  16. 16 Department of Pediatrics, Centre Hospitalier Universitaire de Brest, Brest, France
  17. 17 Department of Pediatric Neurology, ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, The Netherlands
  18. 18 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
  19. 19 Center for Human Genetics, Universitätsklinikum Regensburg, Regensburg, Germany
  20. 20 West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, University of Southampton, Southampton, UK
  21. 21 SW Thames Regional Genetics Service, University of London St George's Molecular and Clinical Sciences Research Institute, London, UK
  22. 22 Département de Génétique, Hôpital Universitaire de Nantes, Nantes, France
  23. 23 UF de Fœtopathologie et Génétique, CHU Nantes, Nantes, France
  24. 24 Department of Pathology, CHU Nantes, Nantes, France
  25. 25 Pediatric Neurology Unit, Universitair Ziekenhuis Antwerpen, Antwerp, Belgium
  26. 26 Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK
  27. 27 Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
  28. 28 Pediatric Neurology, Necker Enfants Malades Hospital, Université de Paris, Paris, France
  29. 29 Embryology and Genetics of Congenital Malformations, Institut Imagine (INSERM UMR-1163), Paris, France
  1. Correspondence to Dr Stefanie Brock, Department of Pathology, Universitair Ziekenhuis Brussel, Brussel, Belgium; Stefanie.Brock{at}vub.be

Abstract

Background Malformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants in GRIN1 or GRIN2B, genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs.

Methods We report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with NMDAR-related MCDs. Neuropathological findings for two individuals with heterozygous variants in GRIN1 are presented. We report the clinical and neuropathological features of one additional individual with homozygous pathogenic variants in GRIN1.

Results Heterozygous variants in GRIN1 and GRIN2B were associated with overlapping severe clinical and imaging features, including global developmental delay, epilepsy, diffuse dysgyria, dysmorphic basal ganglia and hippocampi. Neuropathological examination in two fetuses with heterozygous GRIN1 variants suggests that proliferation as well as radial and tangential neuronal migration are impaired. In addition, we show that neuronal migration is also impaired by homozygous GRIN1 variants in an individual with microcephaly with simplified gyral pattern.

Conclusion These findings expand our understanding of the clinical and imaging features of the ‘NMDARopathy’ spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.

  • Nervous System Malformations
  • Genetics
  • Pathology
  • Radiology
  • Pediatrics

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Anonymised data from this study will be shared by request from any qualified investigator.

https://doi.org/10.1136/jmedgenet-2021-107971

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    Data availability statement

    Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Anonymised data from this study will be shared by request from any qualified investigator.

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    Footnotes

    • Contributors AEF, NB-B and ACJ conceived the work. SB, AL, AEF, SJM and NB-B assisted with data acquisition. SB, AL and AEF drafted the manuscript, which was revised and approved by all. SB and AEF act as guarantor.

    • Funding The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by Wellcome (see Nature PMID: 25533962 or www.ddduk.org/access.html for full acknowledgement). ACJ was funded by an FWO Senior Clinical Investigator Fellowship. SB received funding from the Scientific Fund Willy Gepts. DB is supported by NIHR Research Professorship (RP-2016- 07-011). SFT received funding from the NIH-NINDS (NS111619). YH is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (R01HD082373) and the National Institute of Mental Health (MH127404). SJM is supported by a grant from the National Institute on Aging (R21AG072142). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    • Competing interests SFT is principal investigator on research grants from Biogen and Janssen to Emory; a member of the Scientific Advisory Board for Eumentis, Sage Therapeutics, GRIN2B Foundation and CureGRIN Foundation; co-founder of NeurOp and Agrithera; and coinventor on Emory-owned intellectual property.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.