Abstract
Fragile X Syndrome (FXS) is an X-linked disorder leading to the loss of expression of FMR1-protein product, FMRP. The absence or deficiency of FMRP is thought to result in the characteristic FXS phenotypes, including intellectual disability. Identifying the relationship between FMRP levels and IQ may be critical to better understand underlying mechanisms and advance treatment development and planning. A sample of 143 individuals with FXS (69% male), aged 8-50 years, completed IQ testing and blood draw via venipuncture to determine the relationship between Deviation IQ scores and FMRP levels as well as the distribution of Deviation IQ scores. In both males and females with FXS, higher FMRP levels were associated with higher Deviation IQ. However, this relationship was no longer significant when only examining full mutation, fully-methylated males. Yet, both the full and restricted male samples showed a downward shifted but otherwise normal distribution of Deviation IQ scores. Our findings support and extend previous studies establishing molecular markers of disease severity in FXS as well as provide novel evidence of a "FXS IQ standard curve". This latter finding suggests inter-individual variation in Deviation IQ in FXS, especially among males, may be driven by similar factors known to impact cognitive outcomes in typically-developing individuals. Thus, future work aimed at understanding the mechanisms by which FMRP loss leads to intellectual disability should revisit the biological/genetic, socio-environmental, and epigenetic factors contributing to inter-individual variation in IQ in FXS.