Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B
Open accessAbstract
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.
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Developmental and epileptic encephalopathies
Scheffer, I. E., Zuberi, S., Mefford, H. C., Guerrini, R., & McTague, A. (2024) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00546-6 · Cited by 128 · see citing works
- Authors
- Brock, S., Laquerriere, A., Marguet, F., Myers, S. J., Hongjie, Y., Baralle, D., Vanderhasselt, T., Stouffs, K., Keymolen, K., Kim, S., Allen, J., Shaulsky, G., Chelly, J., Marcorelle, P., Aziza, J., Villard, L., Sacaze, E., de Wit, M. C. Y., Wilke, M., Mancini, G. M. S., Hehr, U., Lim, D., Mansour, S., Traynelis, S. F., Beneteau, C., Denis-Musquer, M., Jansen, A. C., Fry, A. E., & Bahi-Buisson, N.
- Affiliations
- Vrije Universiteit Brussel (BE)
- Normandy Centre for Genomic and Personalized Medicine, INSERM U1245, Rouen, France
- Inserm (FR)
- Emory University (US)
- University of Southampton (GB)
- Universitair Ziekenhuis Brussel (BE)
- Centre National de la Recherche Scientifique (FR)
- Université de Bretagne Occidentale (FR)
- Department of Pathology, University Institute for Cancer, Toulouse, France
- Centre Hospitalier Régional Universitaire de Brest (FR)
- Department of Pediatric Neurology, ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, The Netherlands
- Erasmus MC (NL)
- University Hospital Regensburg (DE)
- Birmingham Women's Hospital (GB)
- University of London (GB)
- Département de Génétique, Hôpital Universitaire de Nantes, Nantes, France
- Centre Hospitalier Universitaire de Nantes (FR)
- Antwerp University Hospital (BE)
- University Hospital of Wales (GB)
- Pediatric Neurology, Necker Enfants Malades Hospital, Université de Paris, Paris, France
- Corresponding author
- Brock, Stefanie
- ORCID
- Brock, Stefanie
- Marguet, Florent
- Myers, Scott J
- Baralle, Diana
- Vanderhasselt, Tim
- Stouffs, Katrien
- Keymolen, Kathelijn
- Allen, James
- Shaulsky, Gil
- Chelly, Jamel
- Villard, Laurent
- Sacaze, Elise
- Wilke, Martina
- Mancini, Grazia Maria Simonetta
- Hehr, Ute
- Lim, Derek
- Mansour, Sahar
- Traynelis, Stephen F
- Jansen, Anna C
- Fry, Andrew E
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2022-04-07
- Volume
- 60
- Issue
- 2
- Pages
- 183-192
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- PMC
- PMC10642159
- OpenAlex
- W4225574618
- Cited by
- 12
- References
- 33
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 7 · 2023: 1
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- HAL (submittedVersion, cc-by-nc)
- Funders
- Biogen
- Emory University
- Wellcome Trust
- National Institute for Health and Care Research (RP-2016-07-011, HICF-1009-003)
- Fonds Wetenschappelijk Onderzoek
- National Institutes of Health
- Medical Research Council (MC_PC_16035)
- National Institute on Aging (R21AG072142)
- National Institute of Mental Health (R21MH127404, MH127404)
- National Institute of Neurological Disorders and Stroke (MH127404, R35NS111619, NS 111619)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD082373)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- malformations of cortical development, GRIN1, NR2B subunit, NMDA receptor, heterozygous mutation, homozygous variant, epilepsy, developmental delay, neuronal migration, microcephaly, neuropathology, fetal brain
- MeSH terms
- Epilepsy, Heterozygote, Homozygote, Humans, Microcephaly, Nerve Tissue Proteins, Receptors, N-Methyl-D-Aspartate
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