Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/17983
Title: GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.
Authors: Platzer, Konrad;Yuan, Hongjie;Schütz, Hannah;Winschel, Alexander;Chen, Wenjuan;Hu, Chun;Kusumoto, Hirofumi;Heyne, Henrike O;Helbig, Katherine L;Tang, Sha;Willing, Marcia C;Tinkle, Brad T;Adams, Darius J;Depienne, Christel;Keren, Boris;Mignot, Cyril;Frengen, Eirik;Strømme, Petter;Biskup, Saskia;Döcker, Dennis;Strom, Tim M;Mefford, Heather C;Myers, Candace T;Muir, Alison M;LaCroix, Amy;Sadleir, Lynette;Scheffer, Ingrid E;Brilstra, Eva;van Haelst, Mieke M;van der Smagt, Jasper J;Bok, Levinus A;Møller, Rikke S;Jensen, Uffe B;Millichap, John J;Berg, Anne T;Goldberg, Ethan M;De Bie, Isabelle;Fox, Stephanie;Major, Philippe;Jones, Julie R;Zackai, Elaine H;Abou Jamra, Rami;Rolfs, Arndt;Leventer, Richard J;Lawson, John A;Roscioli, Tony;Jansen, Floor E;Ranza, Emmanuelle;Korff, Christian M;Lehesjoki, Anna-Elina;Courage, Carolina;Linnankivi, Tarja;Smith, Douglas R;Stanley, Christine;Mintz, Mark;McKnight, Dianalee;Decker, Amy;Tan, Wen-Hann;Tarnopolsky, Mark A;Brady, Lauren I;Wolff, Markus;Dondit, Lutz;Pedro, Helio F;Parisotto, Sarah E;Jones, Kelly L;Patel, Anup D;Franz, David N;Vanzo, Rena;Marco, Elysa;Ranells, Judith D;Di Donato, Nataliya;Dobyns, William B;Laube, Bodo;Traynelis, Stephen F;Lemke, Johannes R
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
Department of Neurophysiology and Neurosensory Systems, Technical University Darmstadt, Darmstadt, Hessen, Germany
Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA
Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
Advocate Children's Hospital, Park Ridge, Illinois, USA
Genetics and Metabolism, Goryeb Children's Hospital, Atlantic Health System, Morristown, New Jersey, USA
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
UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.. Laboratoire de cytogénétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Department of Medical Genetics, Oslo University Hospitals and University of Oslo, Oslo, Norway
Department of Pediatrics, Oslo University Hospitals and University of Oslo, Oslo, Norway
Practice for Human Genetics and CeGaT GmbH, Tübingen, Germany
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, USA
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
Department of Medicine, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia
Department of Genetics, Utrecht University Medical Center, Utrecht, The Netherlands
Department of Paediatrics, Màxima Medical Centre, Veldhoven, The Netherlands
The Danish Epilepsy Centre Filadelfia, Dianalund, Denmark
Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
Departments of Pediatrics, Epilepsy Center and Division of Neurology Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Division of Neurology, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada
Department of Neurological Sciences, Université de Montréal, CHU Ste-Justine, Montreal, Canada..Greenwood Genetic Center, Greenwood, South Carolina, USA
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Centogene AG, Rostock, Germany..
Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
Murdoch Childrens Research Institute and Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia
Department of Neurology, Sydney Children's Hospital, Sydney, New South Wales, Australia
Genome.One, Sydney, New South Wales, Australia
Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands
Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
Department of Child and Adolescent, Neurology Unit, University Hospitals of Geneva, Geneva, Switzerland
The Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland
Research Programs Unit, Molecular Neurology and Neuroscience Center, University of Helsinki, Helsinki, Finland
Department of Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Courtagen Life Sciences, Woburn, Massachusetts, USA..The Center for Neurological and Neurodevelopmental Health and the Clinical Research Center of New Jersey, Voorhees, New Jersey, USA
GeneDx, Gaithersburg, Maryland, USA
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA
Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Ontario, Canada
Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tubingen, Germany
Department of Pediatric Neurology and Center for Developmental Medicine, Olgahospital Stuttgart, Stuttgart, Germany
Hackensack University Medical Center, Hackensack, New Jersey, USA
Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi, USA
Nationwide Children's Hospital, Columbus, Ohio, USA
Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
Lineagen, Inc., Salt Lake City, Utah, USA
Department of Pediatrics, University of South Florida, Tampa, Florida, USA
Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Neurology, University of San Francisco School of Medicine, San Francisco, California, USA
The Ohio State University College of Medicine, Columbus, Ohio, USA
Department of Pediatrics, University of Washington, Seattle, Washington, USA
Department of Neurology, University of Washington, Seattle, Washington, USA
Issue Date: Jul-2017
EDate: 2017-04-04
Citation: Journal of medical genetics 2017; 54(7): 460-470
Abstract: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Data of 48 individuals with de novo GRIN2B variants 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 that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
URI: http://ahro.austin.org.au/austinjspui/handle/1/17983
DOI: 10.1136/jmedgenet-2016-104509
ORCID: 0000-0002-2311-2174
PubMed URL: 28377535
Type: Journal Article
Subjects: channelopathy
clustering of missense variants
epileptic encephalopathy
pathogenic GRIN2B mutations
precision medicine
Appears in Collections:Journal articles

Files in This Item:
There are no files associated with this item.


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.