Johannes R. Lemke, Andrea Eoli, Ilona Krey, Bernt Popp, Vincent Strehlow, Dirk Alexander Wittekind, Anna‐Leena Vuorinen, Hesham Aldhalaan, Sarah Baer, Anne de Saint Martin, Trine Bjørg Hammer, Isabella Herman, Frauke Hornemann, Trine Ingebrigtsen, Damien Lederer, Gaëtan Lesca, Dana Marafie, Mikaël 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 Heyne, Steffen Syrbe
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 .