Abstract summary 

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and autism spectrum disorder. The syndrome is often caused by greatly reduced or absent protein expression from the () gene due to expansion of a 5'-non-coding trinucleotide (CGG) element beyond 200 repeats (full mutation). To better understand the complex relationships among allelotype, methylation status, mRNA expression, and protein (FMRP) levels, FMRP was quantified in peripheral blood mononuclear cells for a large cohort of FXS ( = 154) and control ( = 139) individuals using time-resolved fluorescence resonance energy transfer. Considerable size and methylation mosaicism were observed among individuals with FXS, with FMRP detected only in the presence of such mosaicism. No sample with a minimum allele size greater than 273 CGG repeats had significant levels of FMRP. Additionally, an association was observed between mRNA and FMRP levels in FXS samples, predominantly driven by those with the lowest FMRP values. This study underscores the complexity of allelotypes and FMRP expression and prompts a reevaluation of FXS therapies aimed at reactivating large full mutation alleles that are likely not capable of producing sufficient FMRP to improve cognitive function.

Authors & Co-authors:  Randol Kim Ponzini Tassone Falcon Hagerman Hagerman

Study Outcome 

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