AUTHOR=Pretto Dalyir , Yrigollen Carolyn M. , Tang Hiu-Tung , Williamson John , Espinal Glenda , Iwahashi Chris K. , Durbin-Johnson Blythe , Hagerman Randi J. , Hagerman Paul J. , Tassone Flora 

TITLE=Clinical and molecular implications of mosaicism in FMR1 full mutations

JOURNAL=Frontiers in Genetics

VOLUME=5

YEAR=2014

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2014.00318

DOI=10.3389/fgene.2014.00318

ISSN=1664-8021

ABSTRACT=<p>Expansions of more than 200 CGG repeats (full mutation) in the <italic>FMR1</italic> gene give rise to fragile X syndrome (FXS) through a process that generally involves hypermethylation of the <italic>FMR1</italic> promoter region and gene silencing, resulting in absence of expression of the encoded protein, FMRP. However, mosaicism with alleles differing in size and extent of methylation often exist within or between tissues of individuals with FXS. In the current work, CGG-repeat lengths and methylation status were assessed for eighteen individuals with FXS, including 13 mosaics, for which peripheral blood cells (PBMCs) and primary fibroblast cells were available. Our results show that for both PBMCs and fibroblasts, <italic>FMR1</italic> mRNA and FMRP expression are directly correlated with the percent of methylation of the <italic>FMR1</italic> allele. In addition, Full Scale IQ scores were inversely correlated with the percent methylation and positively correlated with higher FMRP expression. These latter results point toward a positive impact on cognition for full mutation mosaics with lower methylation compared to individuals with fully methylated, full mutation alleles. However, we did not observe a significant reduction in the number of seizures, nor in the severity of hyperactivity or autism spectrum disorder, among individuals with mosaic genotypes in the presentation of FXS. These observations suggest that low, but non-zero expression of FMRP may be sufficient to positively impact cognitive function in individuals with FXS, with methylation mosaicism (lowered methylation fraction) contributing to a more positive clinical outcome.</p>