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

Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B
Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B
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.
Genetics, Nervous System Malformations, Pathology, Pediatrics, Radiology
0022-2593
1-10
Brock, Stefanie
24904683-365c-47f0-8798-7a138a68e092
Laquerriere, Annie
60ecfbee-9670-4988-95c4-f846234feb89
Marguet, Florent
b23b475a-ec20-408e-ac75-ec80df8a567f
Myers, Scott J
23d857fc-05cc-47ad-9462-8ffc92b5dc81
Hongjie, Yuan
853158bf-f29a-41f0-9476-c0ce18c4a330
Baralle, Diana
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Vanderhasselt, Tim
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Stouffs, Katrien
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Keymolen, Kathelijn
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Kim, Sukhan
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Allen, James
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Shaulsky, Gil
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Chelly, Jamel
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Marcorelle, Pascale
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Aziza, Jacqueline
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Villard, Laurent
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Sacaze, Elise
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de Wit, Marie
34317d41-7ed5-4536-bd9c-168c34ff19d7
Wilke, Martina
26c4af7d-afc0-43f5-8729-ea683fa353a2
Mancini, Grazia
ea1d7bef-6f58-47db-8400-eadeff1f11aa
Hehr, Ute
457cf36a-e4d4-439c-a95f-908718e00d68
Lim, Derek
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Mansour, Sahar
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Traynelis, Stephen
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Beneteau, Claire
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Denis-Musquer, Marie
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Jansen, Anna
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Fry, Andrew
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Bahi-Bulsson, Nadia
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Brock, Stefanie
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Laquerriere, Annie
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Marguet, Florent
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Myers, Scott J
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Hongjie, Yuan
853158bf-f29a-41f0-9476-c0ce18c4a330
Baralle, Diana
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Vanderhasselt, Tim
d29ca749-d80f-4999-8502-6eea7a3bbc39
Stouffs, Katrien
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Keymolen, Kathelijn
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Kim, Sukhan
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Allen, James
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Shaulsky, Gil
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Chelly, Jamel
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Marcorelle, Pascale
6ffba654-b2e4-445d-8ab0-4883ee0fe16c
Aziza, Jacqueline
a896f99d-7efa-4582-9e2a-a775ada7cdd9
Villard, Laurent
06ff3959-1bf3-4ce7-8762-f6c08fc63544
Sacaze, Elise
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de Wit, Marie
34317d41-7ed5-4536-bd9c-168c34ff19d7
Wilke, Martina
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Mancini, Grazia
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Hehr, Ute
457cf36a-e4d4-439c-a95f-908718e00d68
Lim, Derek
caefba8b-66a4-44d2-8b5b-73bee24bc693
Mansour, Sahar
fcece354-b435-46fb-8acf-184dad0ed4c2
Traynelis, Stephen
24e00744-1f48-4836-bef3-d463bbc8ab07
Beneteau, Claire
fe021351-de0c-42f1-94a5-d2f8c3701036
Denis-Musquer, Marie
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Jansen, Anna
ebfdc9e2-e0e3-4683-b13a-9af9edd75ac9
Fry, Andrew
60a8a3a9-7d5b-435c-8aaa-1206578c5fdf
Bahi-Bulsson, Nadia
41d96830-4452-4b33-9afe-f956ee741234

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, Wilke, Martina, Mancini, Grazia, Hehr, Ute, Lim, Derek, Mansour, Sahar, Traynelis, Stephen, Beneteau, Claire, Denis-Musquer, Marie, Jansen, Anna, Fry, Andrew and Bahi-Bulsson, Nadia (2022) Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B. Journal of Medical Genetics, 1-10, [107971]. (doi:10.1136/JMEDGENET-2021-107971).

Record type: Article

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.

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GRIN_manuscript_16 March - Accepted Manuscript
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More information

Accepted/In Press date: 16 March 2022
e-pub ahead of print date: 7 April 2022
Additional Information: Publisher Copyright: © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.
Keywords: Genetics, Nervous System Malformations, Pathology, Pediatrics, Radiology

Identifiers

Local EPrints ID: 456082
URI: http://eprints.soton.ac.uk/id/eprint/456082
ISSN: 0022-2593
PURE UUID: 25864f52-e4e1-453c-83a1-cada6a368333
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 26 Apr 2022 11:04
Last modified: 23 Sep 2022 01:40

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Contributors

Author: Stefanie Brock
Author: Annie Laquerriere
Author: Florent Marguet
Author: Scott J Myers
Author: Yuan Hongjie
Author: Diana Baralle ORCID iD
Author: Tim Vanderhasselt
Author: Katrien Stouffs
Author: Kathelijn Keymolen
Author: Sukhan Kim
Author: James Allen
Author: Gil Shaulsky
Author: Jamel Chelly
Author: Pascale Marcorelle
Author: Jacqueline Aziza
Author: Laurent Villard
Author: Elise Sacaze
Author: Marie de Wit
Author: Martina Wilke
Author: Grazia Mancini
Author: Ute Hehr
Author: Derek Lim
Author: Sahar Mansour
Author: Stephen Traynelis
Author: Claire Beneteau
Author: Marie Denis-Musquer
Author: Anna Jansen
Author: Andrew Fry
Author: Nadia Bahi-Bulsson

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