GRIN2A is a highly conserved gene that is according to gnomAD (v2.1.1, https://gnomad.broadinstitute.org/) depleted for missense (Z = 2.83) but not for null variants. Pathogenic heterozygous missense variants are usually 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. GRIN2A null variants are also clearly associated with the typical disease spectrum. This spectrum can be clinically mild and affected individuals often are able to reproduce. As a consequence, GRIN2A null variants are the only pathogenic variants within the GRIN gene family that are frequently found to be inherited.
Several pathogenic variants in GRIN2A have been confirmed to result in either gain or loss of function of the NMDA receptor.
GRIN2A-related neurodevelopmental disorders are inherited in an autosomal dominant manner. The diagnosis of a GRIN2A-related neurodevelopmental disorder is established in a proband by identification of either a heterozygous pathogenic variant or exon or whole-gene deletion of GRIN2A on molecular genetic testing.
GRIN2A