PMID- 35393335
OWN - NLM
STAT- MEDLINE
DCOM- 20230127
LR  - 20231117
IS  - 1468-6244 (Electronic)
IS  - 0022-2593 (Print)
IS  - 0022-2593 (Linking)
VI  - 60
IP  - 2
DP  - 2023 Feb
TI  - Overlapping cortical malformations in patients with pathogenic variants in GRIN1 
      and GRIN2B.
PG  - 183-192
LID - 10.1136/jmedgenet-2021-107971 [doi]
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 'NMDARopathy' spectrum 
      and contribute to our understanding of the likely underlying pathogenic 
      mechanisms leading to MCD in these patients.
CI  - (c) Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and 
      permissions. Published by BMJ.
FAU - Brock, Stefanie
AU  - Brock S
AUID- ORCID: 0000-0002-4137-512X
AD  - Department of Pathology, Universitair Ziekenhuis Brussel, Brussels, Belgium 
      Stefanie.Brock@vub.be.
AD  - Neurogenetics Research Group, Reproduction Genetics and Regenerative Medicine 
      Research Cluster, Vrije Universiteit Brussel, Brussels, Belgium.
FAU - Laquerriere, Annie
AU  - Laquerriere A
AD  - Normandy Centre for Genomic and Personalized Medicine, INSERM U1245, Rouen, 
      France.
AD  - Department of Pathology, Rouen University Hospital, Rouen, France.
FAU - Marguet, Florent
AU  - Marguet F
AD  - Normandy Centre for Genomic and Personalized Medicine, INSERM U1245, Rouen, 
      France.
AD  - Department of Pathology, Rouen University Hospital, Rouen, France.
FAU - Myers, Scott J
AU  - Myers SJ
AD  - Department of Pharmacology and Chemical Biology, Emory University School of 
      Medicine Atlanta, Atlanta, Georgia, USA.
AD  - Center for Functional Evaluation of Rare Variants (CFERV), Emory University 
      School of Medicine Atlanta, Atlanta, Georgia, USA.
FAU - Hongjie, Yuan
AU  - Hongjie Y
AD  - Department of Pharmacology and Chemical Biology, Emory University School of 
      Medicine Atlanta, Atlanta, Georgia, USA.
AD  - Center for Functional Evaluation of Rare Variants (CFERV), Emory University 
      School of Medicine Atlanta, Atlanta, Georgia, USA.
FAU - Baralle, Diana
AU  - Baralle D
AD  - Human Development and Health, University of Southampton, Southampton, UK.
FAU - Vanderhasselt, Tim
AU  - Vanderhasselt T
AD  - Department of Radiology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, 
      Belgium.
FAU - Stouffs, Katrien
AU  - Stouffs K
AUID- ORCID: 0000-0001-8164-5692
AD  - Neurogenetics Research Group, Reproduction Genetics and Regenerative Medicine 
      Research Cluster, Vrije Universiteit Brussel, Brussels, Belgium.
AD  - Center for Reproduction and Genetics, Universitair Ziekenhuis Brussel (UZ 
      Brussel), Brussels, Belgium.
FAU - Keymolen, Kathelijn
AU  - Keymolen K
AD  - Center for Reproduction and Genetics, Universitair Ziekenhuis Brussel (UZ 
      Brussel), Brussels, Belgium.
FAU - Kim, Sukhan
AU  - Kim S
AD  - Department of Pharmacology and Chemical Biology, Emory University School of 
      Medicine Atlanta, Atlanta, Georgia, USA.
AD  - Center for Functional Evaluation of Rare Variants (CFERV), Emory University 
      School of Medicine Atlanta, Atlanta, Georgia, USA.
FAU - Allen, James
AU  - Allen J
AD  - Department of Pharmacology and Chemical Biology, Emory University School of 
      Medicine Atlanta, Atlanta, Georgia, USA.
AD  - Center for Functional Evaluation of Rare Variants (CFERV), Emory University 
      School of Medicine Atlanta, Atlanta, Georgia, USA.
FAU - Shaulsky, Gil
AU  - Shaulsky G
AD  - Department of Pharmacology and Chemical Biology, Emory University School of 
      Medicine Atlanta, Atlanta, Georgia, USA.
AD  - Center for Functional Evaluation of Rare Variants (CFERV), Emory University 
      School of Medicine Atlanta, Atlanta, Georgia, USA.
FAU - Chelly, Jamel
AU  - Chelly J
AD  - Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS UMR 7104, 
      INSERM U1258, Universite de Strasbourg, Strasbourg, France.
AD  - Laboratoire de Diagnostic Genetique, Hopitaux Universitaire de Strasbourg, 
      Strasbourg, France.
FAU - Marcorelle, Pascale
AU  - Marcorelle P
AD  - Service d'Anatomie Pathologique, Centre Hospitalier Universitaire de Brest; 
      Laboratoire Neurosciences de Brest, Universite de Brest, Brest, France.
FAU - Aziza, Jacqueline
AU  - Aziza J
AD  - Department of Pathology, University Institute for Cancer, Toulouse, France.
FAU - Villard, Laurent
AU  - Villard L
AD  - Inserm, Marseille Medical Genetics Center, Aix-Marseille University, Marseille, 
      France.
AD  - Department of Medical Genetics, La Timone Children's Hospital, Marseille, France.
FAU - Sacaze, Elise
AU  - Sacaze E
AD  - Department of Pediatrics, Centre Hospitalier Universitaire de Brest, Brest, 
      France.
FAU - de Wit, Marie C Y
AU  - de Wit MCY
AD  - Department of Pediatric Neurology, ENCORE Expertise Center for Neurodevelopmental 
      Disorders, Erasmus Medical Center, Rotterdam, The Netherlands.
FAU - Wilke, Martina
AU  - Wilke M
AD  - Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The 
      Netherlands.
FAU - Mancini, Grazia Maria Simonetta
AU  - Mancini GMS
AUID- ORCID: 0000-0002-1211-9979
AD  - Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The 
      Netherlands.
FAU - Hehr, Ute
AU  - Hehr U
AD  - Center for Human Genetics, Universitatsklinikum Regensburg, Regensburg, Germany.
FAU - Lim, Derek
AU  - Lim D
AD  - West Midlands Regional Genetics Service and Birmingham Health Partners, 
      Birmingham Women's and Children's Hospitals NHS Foundation Trust, University of 
      Southampton, Southampton, UK.
FAU - Mansour, Sahar
AU  - Mansour S
AUID- ORCID: 0000-0001-6629-4118
AD  - SW Thames Regional Genetics Service, University of London St George's Molecular 
      and Clinical Sciences Research Institute, London, UK.
FAU - Traynelis, Stephen F
AU  - Traynelis SF
AD  - Department of Pharmacology and Chemical Biology, Emory University School of 
      Medicine Atlanta, Atlanta, Georgia, USA.
AD  - Center for Functional Evaluation of Rare Variants (CFERV), Emory University 
      School of Medicine Atlanta, Atlanta, Georgia, USA.
FAU - Beneteau, Claire
AU  - Beneteau C
AD  - Departement de Genetique, Hopital Universitaire de Nantes, Nantes, France.
AD  - UF de Foetopathologie et Genetique, CHU Nantes, Nantes, France.
FAU - Denis-Musquer, Marie
AU  - Denis-Musquer M
AD  - UF de Foetopathologie et Genetique, CHU Nantes, Nantes, France.
AD  - Department of Pathology, CHU Nantes, Nantes, France.
FAU - Jansen, Anna C
AU  - Jansen AC
AUID- ORCID: 0000-0002-3835-2824
AD  - Pediatric Neurology Unit, Universitair Ziekenhuis Antwerpen, Antwerp, Belgium.
FAU - Fry, Andrew E
AU  - Fry AE
AD  - Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
AD  - Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, 
      UK.
FAU - Bahi-Buisson, Nadia
AU  - Bahi-Buisson N
AD  - Pediatric Neurology, Necker Enfants Malades Hospital, Universite de Paris, Paris, 
      France.
AD  - Embryology and Genetics of Congenital Malformations, Institut Imagine (INSERM 
      UMR-1163), Paris, France.
LA  - eng
GR  - R01 HD082373/HD/NICHD NIH HHS/United States
GR  - MC_PC_16035/MRC_/Medical Research Council/United Kingdom
GR  - R21 AG072142/AG/NIA NIH HHS/United States
GR  - RP-2016- 07-011/DH_/Department of Health/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
GR  - R35 NS111619/NS/NINDS NIH HHS/United States
GR  - R21 MH127404/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220407
PL  - England
TA  - J Med Genet
JT  - Journal of medical genetics
JID - 2985087R
RN  - 0 (GRIN1 protein, human)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (NR2B NMDA receptor)
SB  - IM
MH  - Humans
MH  - *Epilepsy
MH  - Heterozygote
MH  - Homozygote
MH  - *Microcephaly
MH  - Nerve Tissue Proteins/genetics
MH  - *Receptors, N-Methyl-D-Aspartate/genetics
PMC - PMC10642159
MID - NIHMS1941580
OTO - NOTNLM
OT  - Genetics
OT  - Nervous System Malformations
OT  - Pathology
OT  - Pediatrics
OT  - Radiology
COIS- Competing interests: SFT is principal investigator on research grants from Biogen 
      and Janssen to Emory; a member of the Scientific Advisory Board for Eumentis, 
      Sage Therapeutics, GRIN2B Foundation and CureGRIN Foundation; co-founder of 
      NeurOp and Agrithera; and coinventor on Emory-owned intellectual property.
EDAT- 2022/04/09 06:00
MHDA- 2023/01/27 06:00
PMCR- 2023/11/13
CRDT- 2022/04/08 05:30
PHST- 2021/05/13 00:00 [received]
PHST- 2022/03/16 00:00 [accepted]
PHST- 2022/04/09 06:00 [pubmed]
PHST- 2023/01/27 06:00 [medline]
PHST- 2022/04/08 05:30 [entrez]
PHST- 2023/11/13 00:00 [pmc-release]
AID - jmedgenet-2021-107971 [pii]
AID - 10.1136/jmedgenet-2021-107971 [doi]
PST - ppublish
SO  - J Med Genet. 2023 Feb;60(2):183-192. doi: 10.1136/jmedgenet-2021-107971. Epub 
      2022 Apr 7.