GRIA1 was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2022 (Ismail et al., PMID: 35675825).
This gene has also been reported in relation to an autosomal dominant 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 split curation for autosomal dominant complex neurodevelopmental disorder (MONDO:0100038) has been curated separately.
A single affected individual with homozygous truncating variants has been reported to date (PMID: 35675825). This individual, born to consanguineous parents, exhibited global developmental delay, with severe intellectual disability and epilepsy. She was non-verbal at the age of 10 years. Behavioral issues included self-injurious behavior and poor sleep. Other features included intermittent divergent strabismus, feeding difficulties, constipation and precocious puberty. Of note, the heterozygous parents of this patient were reported to be unaffected per OMIM (Baralle, D. Personal Communication).
The present gene-disease relationship is further supported by biochemical and non-human model organism 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.
Knockout of gria1 in X. tropicalis resulted in behavior which was similar to seizures in a small subset of tadpoles, as well as impairment of working memory (PMID: 35675825).
In summary, there is limited evidence to support this gene-disease relationship.
Although further evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting date February 8, 2024 (SOP Version 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).
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