Submission Details

GRIN1 was first reported in relation to autosomal recessive (AR) complex neurodevelopmental disorder in 2016 (Bosch et al., PMID: 26350515). Phenotypic features in individuals with biallelic GRIN1 variants include intellectual disability, hypotonia, autism spectrum disorder, stereotypic movements, feeding difficulties and brain abnormalities. Seizures and early death have been reported in individuals with homozygous nonsense variants (PMID 27164704, 35393335). Of note, there have also been many reported cases of individuals with heterozygous missense variants in GRIN1 and complex neurodevelopmental disorder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and molecular mechanism, with the AR presentation being primarily loss of function variants and the AD presentation being primarily missense variants. Therefore, the curations for AD and AR complex neurodevelopmental disorder have been split, and cases with AD GRIN1 variants have been curated separately by the Epilepsy GCEP.

Six homozygous variants reported in six probands in five publications are included in this curation (PMIDs: 34611970, 35393335, 28051072, 27164704, 26350515). The mechanism of pathogenicity appears to be loss of function (PMID: 27164704). This gene-disease relationship is also supported by mouse models (PMIDs: 19794189, 22726567). In summary, there is definitive evidence supporting the relationship between GRIN1 and AR complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date April 4, 2023 (SOP Version 9).