GRIA4 was first reported in detail in relation to autosomal dominant neurodevelopmental disorder with or without seizures and gait abnormalities (MONDO:0060641) in 2017 (Martin et al., PMID:29220673);variants in GRIA4 have been documented previously but without extensive phenotypic details (Lelieveld et al., PMID:27479843). The condition is characterized by developmental delay,intellectual disability, tone abnormalities (mostly in the form of hypertonia or spasticity), abnormal gait, as well as seizures and/or EEG abnormalities in some individuals.
Ten unique missense variants, reported in 10 probands, in 5 publications (PMIDs: 29220673, 27479843, 35518358, 37921875, 38819422) are included in this curation (for a total of 7 points).
The present gene-disease relationship is further supported by experimental evidence such as biochemical evidence and data from a non-human model organism. Specifically, AMPA receptors (AMPARs) are homomeric or heteromeric assemblies of four core subunits (GluA1 - 4). GRIA1, GRIA2 and GRIA3 encoding the GluA1, GluA2 and GluA3 subunits respectively, are known to cause developmental disorders with developmental delay, intellectual disability and autistic features and seizures among the reported phenotypes (PMID: 27080385).
In a mouse model, genetic deficiency of Gria4 either in the form of reduction or complete lack of Gria4 was associated with high frequency spike wave discharges and behavioral arrest, modeling absence epilepsy. The model appeared to be more consistent with recessive inheritance mode with spike wave discharges also observed with lower incidence in the context of heterozygosity (PMID: 18316356).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has been reported.A classification of moderate was approved by the ClinGen Intellectual Disability and Autism Expert Panel GCEP on July 7, 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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