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

Stefanie Brock; Annie Laquerriere; Florent Marguet; Scott J. Myers; Yuan Hongjie; Diana Baralle; Tim Vanderhasselt; Katrien Stouffs; Kathelijn Keymolen; Sukhan Kim; James Allen; Gil Shaulsky; Jamel Chelly; Pascale Marcorelle; Jacqueline Aziza; Laurent Villard; Elise Sacaze; Marie C.Y. De Wit; Martina Wilke; Grazia Maria Simonetta Mancini; Ute Hehr; Derek Lim; Sahar Mansour; Stephen F. Traynelis; Claire Beneteau; Marie Denis-Musquer; Anna C. Jansen; Andrew E. Fry; Nadia Bahi-Buisson

doi:10.1136/jmedgenet-2021-107971

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

Stefanie Brock^*, Annie Laquerriere, Florent Marguet, Scott J. Myers, Yuan Hongjie, Diana Baralle, Tim Vanderhasselt, Katrien Stouffs, Kathelijn Keymolen, Sukhan Kim, James Allen, Gil Shaulsky, Jamel Chelly, Pascale Marcorelle, Jacqueline Aziza, Laurent Villard, Elise Sacaze, Marie C.Y. De Wit, Martina Wilke, Grazia Maria Simonetta ManciniUte Hehr, Derek Lim, Sahar Mansour, Stephen F. Traynelis, Claire Beneteau, Marie Denis-Musquer, Anna C. Jansen, Andrew E. Fry, Nadia Bahi-Buisson

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

9 Citations (Scopus)

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 â € NMDARopathy' spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.

Original language	English
Pages (from-to)	183-192
Number of pages	10
Journal	Journal of Medical Genetics
Volume	60
Issue number	2
Early online date	7 Apr 2022
DOIs	https://doi.org/10.1136/jmedgenet-2021-107971
Publication status	Published - Feb 2023

Bibliographical note

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.

Publisher Copyright:
© 2022 BMJ Publishing Group. All rights reserved.

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10.1136/jmedgenet-2021-107971

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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., ... Bahi-Buisson, N. (2023). Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B. Journal of Medical Genetics, 60(2), 183-192. https://doi.org/10.1136/jmedgenet-2021-107971

@article{9d56e942946a4e58bdc2b44141461199,

title = "Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B",

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 {\^a} € NMDARopathy' spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.",

author = "Stefanie Brock and Annie Laquerriere and Florent Marguet and Myers, {Scott J.} and Yuan Hongjie and Diana Baralle and Tim Vanderhasselt and Katrien Stouffs and Kathelijn Keymolen and Sukhan Kim and James Allen and Gil Shaulsky and Jamel Chelly and Pascale Marcorelle and Jacqueline Aziza and Laurent Villard and Elise Sacaze and {De Wit}, {Marie C.Y.} and Martina Wilke and Mancini, {Grazia Maria Simonetta} and Ute Hehr and Derek Lim and Sahar Mansour and Traynelis, {Stephen F.} and Claire Beneteau and Marie Denis-Musquer and Jansen, {Anna C.} and Fry, {Andrew E.} and Nadia Bahi-Buisson",

note = "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. Publisher Copyright: {\textcopyright} 2022 BMJ Publishing Group. All rights reserved.",

year = "2023",

month = feb,

doi = "10.1136/jmedgenet-2021-107971",

language = "English",

volume = "60",

pages = "183--192",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "2",

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Brock, S, Laquerriere, A, Marguet, F, Myers, SJ, 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, MCY , Wilke, M , Mancini, GMS, Hehr, U, Lim, D, Mansour, S, Traynelis, SF, Beneteau, C, Denis-Musquer, M, Jansen, AC, Fry, AE & Bahi-Buisson, N 2023, 'Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B', Journal of Medical Genetics, vol. 60, no. 2, pp. 183-192. https://doi.org/10.1136/jmedgenet-2021-107971

TY - JOUR

T1 - Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B

AU - Brock, Stefanie

AU - Laquerriere, Annie

AU - Marguet, Florent

AU - Myers, Scott J.

AU - Hongjie, Yuan

AU - Baralle, Diana

AU - Vanderhasselt, Tim

AU - Stouffs, Katrien

AU - Keymolen, Kathelijn

AU - Kim, Sukhan

AU - Allen, James

AU - Shaulsky, Gil

AU - Chelly, Jamel

AU - Marcorelle, Pascale

AU - Aziza, Jacqueline

AU - Villard, Laurent

AU - Sacaze, Elise

AU - De Wit, Marie C.Y.

AU - Wilke, Martina

AU - Mancini, Grazia Maria Simonetta

AU - Hehr, Ute

AU - Lim, Derek

AU - Mansour, Sahar

AU - Traynelis, Stephen F.

AU - Beneteau, Claire

AU - Denis-Musquer, Marie

AU - Jansen, Anna C.

AU - Fry, Andrew E.

AU - Bahi-Buisson, Nadia

N1 - 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. Publisher Copyright: © 2022 BMJ Publishing Group. All rights reserved.

PY - 2023/2

Y1 - 2023/2

N2 - 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 â € NMDARopathy' spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.

AB - 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 â € NMDARopathy' spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.

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U2 - 10.1136/jmedgenet-2021-107971

DO - 10.1136/jmedgenet-2021-107971

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C2 - 35393335

AN - SCOPUS:85128529767

SN - 0022-2593

VL - 60

SP - 183

EP - 192

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

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ER -

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

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