Identification of rare missense variants of ionotropic glutamate receptor N-methyl-D-aspartate 2 genes in patients with schizophrenia

Schizophrenia is a chronic mental disorder characterized by abnormal synaptic connectivity. N-methyl-D-aspartate receptors (NMDARs) are essential for synaptic transmission and plasticity, and rare variants in the genes encoding NMDARs are linked to neurodevelopmental disorders. In this study, we examined rare pathogenic mutations in four GRIN2 genes, which encode the NMDAR subunit 2, in patients with schizophrenia using ion semiconductor technology and PCR-based fluorescence-based cycle sequencing. We identified 10 novel ultra-rare missense mutations in the GRIN2 genes, none of which were found in the GnomAD_genomes and the Taiwan BioBank. These findings suggest that ultra-rare pathogenic mutations may be present in some individuals with schizophrenia, supporting the existence of rare coding variants of synapse-associated genes that contribute to the genetic architecture of schizophrenia. Future research should explore the in-vitro and in-vivo effects of the identified mutations on the pathophysiology of schizophrenia for further insights.