Reclassification of the GRIA3 splice-site variant in an X-linked family with intellectual disability and psychiatric symptoms
TL;DR
This variant is the first reported, enriching the database and providing additional evidence to support genetic counselling and prenatal diagnosis, and is the first reported to lead to exon 2 skipping of GRIA3.
Abstract
Background The GRIA3 gene is located on the X chromosome and encodes a subunit (GluR3) of the a-amino-3- hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR). The pathogenic variants of GRIA3 are mostly associated with neurodevelopmental disorders. Patients were overwhelmingly male and presented mainly with intellectual disability, dystonia, epilepsy and other symptoms. Methods In this study, we reported a pedigree that carried a novel splicing site variant of GRIA3 (c.268 + 1G>C) by whole exome sequencing (WES) and co-segregation analysis. Three affected family members (two males and one female) not only showed intellectual disability but also presented significant psychiatric symptoms and spatial memory deficits. The minigene assay further confirmed that this variant lead to exon 2 skipping. Results According to ACMG guidelines, We reclassified previously variant of unknown significance (VUS) into “likely pathogenic” through co-segregates analysis and minigene assay. Conclusion It is worth noting that, unlike previous reports, our patients mainly manifested as intellectual disability combined with psychiatric symptoms, expanding the known phenotypic spectrum of GRIA3 gene. Moreover, this variant is the first reported, enriching the database and providing additional evidence to support genetic counselling and prenatal diagnosis.