GRIN2A null variants confer a high risk for early-onset schizophrenia and other mental disorders and potentially enable precision therapy

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<sub>null</sub>) 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<sub>missense</sub>). In our cohort, GRIN2A<sub>null</sub>-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<sub>null</sub>-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<sub>null</sub>-related mental disorders, all of whom experienced improvements of their neuropsychiatric phenotype. GRIN2A<sub>null</sub> 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<sub>null</sub>.

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Publication Details

Journal
Molecular Psychiatry
Published
2025-10-14
DOI
https://doi.org/10.1038/s41380-025-03279-4
Citations
3
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
Field-Weighted Citation Impact
5.45

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article

GRIN2A null variants confer a high risk for early-onset schizophrenia and other mental disorders and potentially enable precision therapy

Anna‐Leena Vuorinen, Trine Bjørg Hammer, Sarah Weckhuysen, Juliette Piard et al.
3 citations
Molecular Psychiatry
Genetics and Neurodevelopmental Disorders
5.45
article

GRIN2A null variants confer a high risk for early-onset schizophrenia and other mental disorders and potentially enable precision therapy

Anna‐Leena Vuorinen, Trine Bjørg Hammer, Sarah Weckhuysen, Juliette Piard, Dana Marafie, Mikaël Mathot, Dirk Alexander Wittekind, Henrike Heyne, Tim A. Benke, Ilona Krey, Stephen F. Traynelis, Isabella Herman, Anup D. Patel, Gaëtan Lesca, Hesham Aldhalaan, Jill Anne Rosenfeld, Helenius J. Schelhaas, Johannes R. Lemke, Alessandro Ascani Orsini, Damien Lederer, Anne de Saint Martin, Sarah Baer, Frauke Hornemann, Danique R.M. Vlaskamp, Vincent Strehlow, Bernt Popp, Rikke S. Møller, Pierangelo Veggiotti, Steffen Syrbe, Andrea Eoli, Trine Ingebrigtsen, Chelsey Stillman
article en
3 citations

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<sub>null</sub>) 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<sub>missense</sub>). In our cohort, GRIN2A<sub>null</sub>-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<sub>null</sub>-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<sub>null</sub>-related mental disorders, all of whom experienced improvements of their neuropsychiatric phenotype. GRIN2A<sub>null</sub> 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<sub>null</sub>.

Molecular PsychiatryVol. 31(1)
Université Claude Bernard Lyon 1 (FR), University of Pisa (IT), Oslo University Hospital (NO), Nationwide Children's Hospital (US), University Medical Center Groningen (NL), University of Helsinki (FI), Hasso Plattner Institute (DE), University of Antwerp (BE), Emory University (US), Inserm (FR), Tampere University (FI), University of Potsdam (DE), Université de Bourgogne (FR), University of Southern Denmark (DK), Lyon College (US), Baylor College of Medicine (US), University of Milan (IT), Heidelberg University (DE), King Faisal Specialist Hospital & Research Centre (SA), University Hospital Heidelberg (DE), Copenhagen University Hospital (DK), Rigshospitalet (DK), Kuwait University (KW), CHU Dinant Godinne UCL Namur (BE), Institute of Pathology and Genetics (BE), Hospices Civils de Lyon (FR), Antwerp University Hospital (BE), Finland University (FI), University Hospital Leipzig (DE), VIB-UAntwerp Center for Molecular Neurology (BE), Institute for Molecular Medicine Finland (FI), Ospedale dei Bambini Vittore Buzzi (IT), Stichting Epilepsie Instellingen Nederland (NL), Klinikum Chemnitz (DE), Baylor Genetics (US), Hôpital Civil, Strasbourg (FR), University of Colorado Anschutz Medical Campus (US), Université de Strasbourg (FR), Université de Franche-Comté (FR), University of Colorado Denver (US), Leipzig University (DE), Icahn School of Medicine at Mount Sinai (US)
Simons Foundation Autism Research Initiative, Deutsche Forschungsgemeinschaft, Fonds Wetenschappelijk Onderzoek, National Institutes of Health
Openalex Percentile: Top 4%
Genetics and Neurodevelopmental Disorders
5.45
DOIOpen Access PDFOpenAlex
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