Submission Details

The GRIA2 gene is located on chromosome 4 at 4q32.1 and encodes the glutamate ionotropic receptor AMPA type subunit 2 protein which functions as a ligand-activated ion channel involved in predominantly excitatory synaptic transmission in mammalian brain. GRIA2 was first reported in relation to autosomal dominant neurodevelopmental disorder with language impairment and behavioral abnormalities in 2019 (Salpietro et al., PMID: 31300657), and is characterized by intellectual disability and neurodevelopmental abnormalities including autism spectrum disorder, speech impairment, developmental regression, Rett syndrome-like features such as head growth deceleration and stereotyped hand movements, and seizures or developmental epileptic encephalopathy. Other reported features include gait disturbances and inability to walk; dystonia; spasticity; joint laxity; hypotonia; ocular concerns; behavioral concerns including obsessive-compulsive behaviors, head banging, and self-injury; sleep disturbances; and cerebellar atrophy and other brain abnormalities. Onset of features occurs in infancy or childhood, and early development may be normal. Ten variants, including seven missense variants, one in-frame deletion and two frameshift variants that have been reported in 12 probands in three publications are included in this curation (PMID: 31300657; Zhou et al., 2021, PMID: 34899870; Latsko et al., 2022, PMID: 35534222). All of these variants occurred de novo and were absent from gnomAD. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by expression, biochemical function, and mouse models. There is neuronal expression of GRIA2 in brain regions. The glutamate ionotropic receptor AMPA type subunits encoded by GRIA1, GRIA3 and GRIA4 have also been associated with autosomal dominant neurodevelopmental disorders. Both homozygous knock-out mice and gain of function knock-in mice expressing a non-desensitising gria2 variant partially recapitulate some aspects of the clinical features (Uhlen et al., 2015, PMID: 25613900; Jia et al., 1996, PMID: 8938126; Christie et al., 2010, PMID: 20439731). In summary, there is definitive evidence to support the relationship between GRIA2 and autosomal dominant GRIA2-neurodevelopmental disorder with language impairment and behavioral abnormalities. 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 Syndromic Disorders GCEP on the meeting date 11.18.2022 (SOP Version 9.0).