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Disease-causing variants in genes encoding subunits of the N-methyl-D-aspartate receptor (NMDAR) are an important contributor to neurodevelopmental disorders. While individually rare, GRIN-related disorders due to disease-causing variants in GRIN1, GRIN2A, GRIN2B or GRIN2D collectively represent 5% of all individuals with a positive genetic diagnosis in our ongoing natural history of genetic epilepsies and neurodevelopmental disorders at the Children’s Hospital of Philadelphia.
By systematically assessing the disease course of individuals with GRIN-related disorders in this cohort, we delineated shared and distinct phenotypic features in this disease group in comparison to other genetic epilepsies and neurodevelopmental disorders using large-scale electronic medical record data.
In our overall cohort of 800 individuals with more than 100 distinct genetic etiologies in 250 individuals, the 12 individuals with GRIN-related disorders showed 32 specific gene-phenotype associations that stood out from the remainder of the cohort. These included associations of GRIN2A and dyslexia
(p=0.005), GRIN1 with absent speech (p= 0.008) and GRIN1 with generalized hypotonia (p=0.009) as the three most significant findings. Both GRIN2A and GRIN2B displayed an association with focal impaired awareness seizures (p=0.03), while GRIN2B was associated with epileptic encephalopathy
(p=0.02) but no specific seizure types. We did not find an association between GRIN-related disorders and the use of specific anti-seizure medications. Our data provide a general overview how GRIN associated disorders relate to the wider range of genetic epilepsies and neurodevelopmental disorders,
which is an important prerequisite for understanding the specificity of phenotypic features and outcome measures for precision medicine trials.