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

Brock, Stefanie, Laquerriere, Annie, Marguet, Florent, Myers, Scott J., Hongjie, Yuan, Baralle, Diana, Vanderhasselt, Tim, Stouffs, Katrien, Keymolen, Kathelijn, Kim, Sukhan, Allen, James, Shaulsky, Gil, Chelly, Jamel, Marcorelle, Pascale, Aziza, Jacqueline, Villard, Laurent, Sacaze, Elise, de Wit, Marie C. Y., Wilke, Martina, Mancini, Grazia Maria Simonetta, Hehr, Ute, Lim, Derek, Mansour, Sahar, Traynelis, Stephen F., Beneteau, Claire, Denis-Musquer, Marie, Jansen, Anna C., Fry, Andrew E. ORCID: and Bahi-Buisson, Nadia 2023. Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B. Journal of Medical Genetics 60 (2) , pp. 183-192. 10.1136/jmedgenet-2021-107971

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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. 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: BMJ Publishing Group
ISSN: 0022-2593
Date of First Compliant Deposit: 20 April 2022
Date of Acceptance: 16 March 2022
Last Modified: 18 Nov 2023 23:02

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