Molecular characteristics

GRIN2B is a highly conserved gene that is according to gnomAD (v2.1.1, depleted for both missense (Z = 5.42) and null variants (pLI = 1.00; LOEUF = 0.06). 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. GRIN2B null variants are similarly associated with GRIN2B-related neurodevelopmental disorder and also generally of de novo origin.

Several pathogenic missense variants in GRIN2B have been confirmed to result in either gain or loss of function of the NMDA receptor.

GRIN2B-related neurodevelopmental disorders are inherited in an autosomal dominant manner. The diagnosis of a GRIN2B-related neurodevelopmental disorder is established in a proband by identification of either a heterozygous pathogenic variant or exon or whole-gene deletion of GRIN2B on molecular genetic testing.