GRIA1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2012 (de Ligt et al., PMID: 23033978). The condition is characterized by developmental delay/intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder and other behavioral manifestations. Epilepsy has also been reported less frequently.
This gene has also been reported in relation to an autosomal recessive intellectual developmental disorder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we determined that there were two distinct disorders with different inheritance patterns and mechanisms. Therefore, the following disease entities have been split into two disease entities, autosomal dominant complex neurodevelopmental disorder (MONDO:0100038) and autosomal recessive complex neurodevelopmental disorder (MONDO:0100038). The autosomal recessive complex neurodevelopmental disorder (MONDO:0100038) has been curated separately.
Seven unique missense variants, reported in 12 probands, in 8 publications (PMIDs: 23033978, 28628100, 35675825, 31398340, 35813072, 35982159, 37921875, 35887114) are included in this curation. Two additional unique missense variants were not scored as per GCEP’s decision due to limited testing methodology (PMID: 28628100). Additional individuals have been reported but were not scored due to inclusion of the same proband in more than one publication (PMIDs: 35675825, 30504930, 37921875), possible overlap of published cohorts (PMIDs: 35982159, 25363760), unaffected status (PMID: 35982159), unavailable phenotype (PMID: 37921875), lack of information on the testing method, functional studies not supportive of a deleterious effect of the variant (PMID: 35675825), or benign classification of the variant as concluded by the authors (PMID: 37543562).
Both gain- and loss-of-function variants have been reported as the mechanism of pathogenicity, the former effect applying to the recurrent p.Ala636Thr (NM_000827.4:c.1906G>A) variant (PMIDs: 28628100, 35675825). To date, there is no report of affected individuals with heterozygous truncating variants. The parents of a proband, homozygous for a nonsense variant (PMID 35675825) have been reported to be unaffected, per OMIM (Baralle, D. Personal Communication).
The present gene-disease relationship is further supported by biochemical evidence. Specifically, AMPA receptors (AMPARs) are homomeric or heteromeric assemblies of four core subunits (GluA1 - 4). GRIA2 and GRIA3 encoding the GluA2 and GluA3 subunits respectively, are known to cause developmental disorders with developmental delay, intellectual disability, autistic features and seizures among the reported phenotypes.
In summary, there is moderate evidence to support the relationship between GRIA1 and autosomal dominant complex neurodevelopmental disorder gene-disease relationship. While further evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on February 8, 2024 (SOP 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.