The most likely causal variant identified was a novel missense variant in the X-linked GRIA3 gene, which has been implicated in intellectual disability.
Ten genes (i.e., ZNF711, SRPX2, RAB40AL, MID2, ACSL4, PAK3, UBE2A, UPF3B, CUL4B, and GRIA3) in the duplication interval have been associated with mental retardation.
Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition.
Xq25 duplications encompassing GRIA3 and STAG2 genes in two families convey recognizable X-linked intellectual disability with distinctive facial appearance.
Taken together with previous findings of GRIA3 disruptions in the patients with MR, our study strengthens the idea that GRIA3 is a candidate gene for X-linked MR and that severely reduced GRIA3 expression results in MR.
No gene contained in this interval has been so far associated with nonsyndromic mental retardation, except for GRIA3, disrupted by a balanced translocation in a female patient with bipolar affective disorder and mental retardation.
The X-chromosome breakpoint in a female patient with a balanced translocation t(X;12)(q24;q15), bipolar affective disorder and mental retardation was mapped within the glutamate receptor 3 (GRIA3) gene by fluorescence in situ hybridization.