Abstracts

Rationale: We aimed to determine the phenotypic spectrum of disorders caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate the functional consequences of the underlying mutations.Methods: For this, we evaluated gene panel and exome sequencing data of 1443 individuals with neurodevelopmental disorders for mutations in GRIN1. Identified and previously described de novo mutations were investigated for functional consequences in Xenopus laevis oocytes.Results: We identified GRIN1 de novo mutations in 13 individuals with intellectual disability. An additional heterozygous GRIN1 variant was associated with idiopathic focal (rolandic) epilepsy and another homozygous variant segregated with severe intellectual disability within a family. Furthermore, we reviewed and analyzed the phenotypes of eight previously reported GRIN1 cases. All 21 GRIN1 de novo mutations resulted in a distinct phenotype of severe intellectual disability with absent speech profound developmental delay, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, and epilepsy. Mutations cluster within transmembrane segments and resulted in loss of channel function of varying severity with a dominant-negative effect.Conclusions: De novo GRIN1 mutations account for approximately 1% of cases with severe intellectual disability. The presence of cortical visual impairment and movement disorders discriminates GRIN1-associated disorders from other genetic NMDA receptor encephalopathies such as GRIN2A- and GRIN2B-associated disorders. Despite variability of functional consequences of the identified GRIN1 mutations, the resulting clinical phenotype appears to be relatively homogeneous and recognizable.