Molecular characteristics

GRIN1 is a highly conserved gene that is according to gnomAD (v2.1.1, depleted for both missense (Z = 6.22) and null variants (pLI = 0.98; LOEUF = 0.31). Pathogenic heterozygous missense variants are generally of de novo origin and appear to cluster within functionally relevant domains, i.e., S1 and S2 ligand binding sites, transmembrane domains as well as linker regions in between, with sparing of amino- as well as C-terminal domains. Several pathogenic missense variants in GRIN1 have been confirmed to result in either gain or loss of function of the NMDA receptor.

Despite high constraint metrics, null variants have thus far not been associated with disease. In fact, some individuals with heterozygous null variants in GRIN1 have been reported to not have any clinically relevant phenotype.  So far, one family with a homozygous GRIN1 null variant leading to fatal epileptic encephalopathy has been described, illustrating that null variants may still contribute to GRIN1-related neurodevelopmental disorder if affecting both alleles. Despite the observation, of two families with homozygous rare missense variants, autosomal recessive GRIN1-related neurodevelopmental disorder due to missense is not yet undoubtedly confirmed.
Thus, GRIN1-related neurodevelopmental disorders are usually inherited in an autosomal dominant manner.
The diagnosis of a GRIN1-related neurodevelopmental disorder is established in a proband by identification of either a heterozygous pathogenic variant or exon or whole-gene deletion of GRIN1 on molecular genetic testing.