Missense variants of GRIN1, GRIN2A, and GRIN2B cause similar syndromes with varying severity of intellectual impairment, autism, epilepsy, and motor dysfunction.
Fragile X syndrome (FXS) is an inherited intellectual impairment that results from the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein that regulates mRNA translation at synapses.
Fragile X Syndrome (FXS) is the main genetic cause of autism and intellectual deficiency resulting the absence of the Fragile X Mental Retardation Protein (FMRP).
Fragile X syndrome, the most common inherited cause of intellectual impairment and the most common single gene associated with autism, generally occurs for fragile X mental retardation 1 (FMR1) alleles that exceed 200 CGG repeats (full-mutation range).
A loss-of-function mutation in the FMR1 gene leads to subtle changes in neural development and subsequent mental impairment characteristic of FX. hNPCs were isolated from fetal cortex carrying the FMR1 mutation to determine whether aberrations occur in their proliferation and differentiation.
The protein product, FMRP, is highly expressed in neurons of the normal mammalian brain, and absent or in low levels in leukocytes from individuals with fragile X (FraX)-associated mental impairment.
Pathogenicity of MEF2C overexpression is still unclear as only four patients with mild intellectual deficiency carrying 5q14.3 microduplications containing MEF2C are described in the literature.
By combining the clinical data of all patients with MEF2C point mutations published so far with the phenotype of our patient, a targeted search for MEF2C mutations could be applied to patients with a severe intellectual deficiency associated with absence of language and hypotonia, strabismus, and epilepsy (started after 6 months, often well controlled by valproate).
We conclude that the excess of intermediate and premutation sized alleles for FRAXA may well be a contributing factor to the boys' mental impairment, while that for FRAXE may be a chance finding.