GRIN2A null variants confer a high risk for early-onset schizophrenia and other mental disorders and potentially enable precision therapy
Year: 2025
Type: article
Study design: Observational Study
Abstract: Rare genetic factors have been shown to substantially contribute to mental illness, but so far, no precision treatments for mental disorders have been described. It was recently identified that rare variants in GRIN2A encoding the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR) confer a substantial risk for schizophrenia. To determine the prevalence of mental disorders among individuals with GRIN2A -related disorders, we enquired the presence of psychiatric symptoms in 235 individuals with pathogenic variants in GRIN2A who had previously enrolled in our global GRIN registry. We identified null variants in GRIN2A ( GRIN2A null ) to be significantly associated with a broad spectrum of mental disorders including schizophrenia compared to a longitudinal population cohort (FinRegistry) as well as missense variants ( GRIN2A missense ). In our cohort, GRIN2A null -related mental disorders manifest in early childhood or adolescence, which is substantially earlier than the average adult onset in the general population. In 68% of co-incident epilepsy and mental disorder, mental disorders start after epilepsy offset and the age of epilepsy offset correlated with mental disorder onset. GRIN2A null -related phenotypes appear to occasionally even manifest as isolated mental disorder, i.e. as schizophrenia or mood disorder without further GRIN2A -specific symptoms, such as intellectual disability and/or epilepsy. As L-serine is known to mediate co-agonistic effects on the NMDAR, we applied it to four individuals with GRIN2A null -related mental disorders, all of whom experienced improvements of their neuropsychiatric phenotype. GRIN2A null appears to be the first monogenic cause of early-onset and even isolated mental disorders, such as early-onset schizophrenia. Genetic testing should be considered in the diagnostic work-up of affected individuals to improve diagnosis and potentially offer personalized treatment as increasing brain concentrations of NMDAR co-agonists appears to be a promising precision treatment approach successfully targeting deficient glutamatergic signaling in individuals with mental disorders, i.e. due to GRIN2A null .
Source: Molecular Psychiatry
Authors: Johannes R. Lemke, Andrea Eoli, Ilona Krey, Bernt Popp, Vincent Strehlow, Dirk A. Wittekind, Anna-Leena Vuorinen, Hesham M. Aldhalaan, Sarah Baer, Anne de Saint Martin, Trine B. Hammer, Isabella Herman, Frauke Hornemann, Trine Ingebrigtsen, Damien Lederer, Gaetan Lesca, Dana Marafie, Mikael Mathot, Jill A. Rosenfeld, Rikke S. Møller, Helenius J. Schelhaas, Chelsey Stillman, Alessandro Orsini, Anup D. Patel, Juliette Piard, Pierangelo Veggiotti, Danique R. M. Vlaskamp, Sarah Weckhuysen, Stephen F. Traynelis, Tim A. Benke, Henrike O. Heyne, Steffen Syrbe
Institutions: University Hospital Leipzig, Leipzig University, Hasso Plattner Institute, University of Potsdam, Icahn School of Medicine at Mount Sinai, University of Helsinki, Tampere University, Institute for Molecular Medicine Finland, University of Tampere, King Faisal Specialist Hospital & Research Centre, Hôpitaux Universitaires de Strasbourg, Copenhagen University Hospital, Rigshospitalet, Baylor College of Medicine, Klinikum Chemnitz, Oslo University Hospital, Institute of Pathology and Genetics, Lyon 1 Université, Kuwait University, Baylor Genetics, University of Southern Denmark, Stichting Epilepsie Instellingen Nederland, University of Colorado Anschutz, University of Pisa, Nationwide Children's Hospital, The Ohio State University, Inserm, Université de Bourgogne, Centre de recherche Translationnelle en Médecine moléculaire, Université de Franche-Comté, University of Milan, Ospedale dei Bambini Vittore Buzzi, University Medical Center Groningen, University of Antwerp, Antwerp University Hospital, VIB-UAntwerp Center for Molecular Neurology, Emory University, Heidelberg University
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,490
Funders: Simons Foundation, Ohio State University, Emory University, Nationwide Children's Hospital, Helsingin Yliopisto, Università degli Studi di Milano, Simons Foundation Autism Research Initiative, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, King Faisal Specialist Hospital and Research Centre, Gentofte Hospital, Fonds Wetenschappelijk Onderzoek, Universität Potsdam, Kuwait University, Université de Bourgogne, Universitair Medisch Centrum Groningen, Rigshospitalet, Syddansk Universitet, Université Claude Bernard Lyon 1, Università di Pisa, Universiteit Antwerpen, Université de Franche-Comté, Universitair Ziekenhuis Antwerpen, Stichting Epilepsie Instellingen Nederland, National Institutes of Health, School of Medicine, Emory University, Department of Artificial Intelligence, Korea University, Faculty of Medicine and Health, University of Sydney, National Institute of Neurological Disorders and Stroke
Awards: Increasing diagnostic yield in genetic childhood onset epilepsies through advanced multi-omics methods and improving mechanistic insights through the study of microglia-containing brain organoids, G3326295708, Nutzung genomischer Daten zur Gewinnung biologischer Erkenntnisse zur Entstehung und Diagnose von Epilepsie, G5884510348, Glutamate receptors and human neurological disease
OpenAlex ID: W4415137993