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Journal Articles Journal of Medical Genetics Year : 2022

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

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

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.

Dates and versions

hal-03949474 , version 1 (20-01-2023)

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Cite

Stefanie Brock, Annie Laquerriere, Florent Marguet, Scott Myers, Yuan Hongjie, et al.. Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B. Journal of Medical Genetics, 2022, pp.jmedgenet-2021-107971. ⟨10.1136/jmedgenet-2021-107971⟩. ⟨hal-03949474⟩

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