Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B

• Type of Material: Article
• Authors: Stefanie Brock, Universitair Ziekenhuis Brussel; Annie Laquerriere, Rouen University; Florent Marguet, Rouen University; Scott J Myers, Emory University; Hongjie Yuan, Emory University; Diana Baralle, University of Southampton; Tim Vanderhasselt, Universitair Ziekenhuis Brussel; Katrien Souffs, Vrije Universiteit Brussel; Kathelijn Keymolen, Universitair Ziekenhuis Brussel; Sukhan Kim, Emory University; James Allen, Emory University; Gil Shaulsky, Emory University; Jamel Chelly, Université de Strasbourg; Pascale Marcorelle, Universitaire de Brest; Jacqueline Aziza, University Institute for Cancer, Toulouse; Laurent Villard, Aix-Marseille University; Elise Sacaze, Universitaire de Brest; Marie C.Y. de Wit, Erasmus Medical Center; Martina Wilke, Erasmus Medical Center; Grazia Maria Simonetta Mancini, Erasmus Medical Center; Ute Hehr, Universitätsklinikum Regensburg; Derek Lim, University of Southampton; Sahar Mansour, University of London; Stephen Traynelis, Emory University; Claire Beneteau, Universitaire de Nantes; Marie Denis-Musquer, CHU Nantes; Anna C. Jansen, Universitair Ziekenhuis Antwerpen; Andrew E. Fry, University Hospital of Wales; Nadia Bahi-Buisson, Université de Paris
• Language: English
• Date: 2022-04-07
• Publisher: BMJ
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2023 BMJ
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): https://doi.org/10.1136/jmedgenet-2021-107971
• Title of Journal or Parent Work: Journal of Medical Genetics
• Volume: 60
• Issue: 2
• Start Page: 183
• End Page: 192
• Grant/Funding Information: 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).
• Keywords: GRIN2B; Malformations of cortical development; GRIN1
• Research Categories: Biology, Neuroscience; Biology, Genetics

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.