title: GRIN2Bencephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.
abstract: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects ofGRIN2Bencephalopathy and explored potential prospects of personalised medicine.
  
  
  
  Data of 48 individuals with de novoGRIN2Bvariants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.
  
  
  
  Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.
  
  
  
  In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence thatGRIN2Bencephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
authors.affiliation: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
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authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia, USA.|Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Hongjie
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authors.lastname: Yuan
authors.affiliation: Department of Neurophysiology and Neurosensory Systems, Technical University Darmstadt, Darmstadt, Hessen, Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Schütz
authors.affiliation: Department of Neurophysiology and Neurosensory Systems, Technical University Darmstadt, Darmstadt, Hessen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Winschel
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia, USA.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia, USA.
authors.forename: Hirofumi
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authors.lastname: Kusumoto
authors.affiliation: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
authors.forename: Henrike O
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authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
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authors.affiliation: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
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authors.affiliation: INSERM, U 1127, Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR 7225, Institut du cerveau et de la moelle épinière (ICM), Paris, France.|Département de Génétique, Centre de Référence des Déficiences Intellectuelles de Causes Rares, GRC UPMC "Déficiences Intellectuelles et Autisme", Hôpital de la Pitié-Salpêtrière, Paris, France.
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authors.affiliation: Department of Neurology, University of San Francisco School of Medicine, San Francisco, California, USA.
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authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.|Department of Pediatrics, University of Washington, Seattle, Washington, USA.|Department of Neurology, University of Washington, Seattle, Washington, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Department of Neurophysiology and Neurosensory Systems, Technical University Darmstadt, Darmstadt, Hessen, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Laube
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia, USA.|Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Stephen F
authors.initials: SF
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authors.affiliation: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
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mesh_terms: D001927:Brain Diseases / Q000188:drug therapy / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008559:Memantine / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D059906:Neuroimaging; D010641:Phenotype; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D008559:Memantine
keywords: channelopathy; clustering of missense variants; epileptic encephalopathy; pathogenic GRIN2B mutations; precision medicine