Characterizing fragile x syndrome in the human brain

The National Institute of Child Health and Human Development awarded $429,000 to The Regents Of The University Of Colorado (University of Colorado-Denver) on August 14, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to characterize Fragile X Syndrome in the human brain using post-mortem human tissue.

The research team will study cell-type-specific gene expression in Fragile X Syndrome human brain tissue and investigate length and methylation mosaicism phenomena unique to the trinucleotide repeat expansion that could be harnessed therapeutically. The work directly examines mechanisms and consequences of the pathogenic repeat expansion at the FMR1 locus in human tissue, addressing the inadequacy of model systems in capturing the full extent of cellular pathophysiology associated with the disorder. The research has implications for understanding Fragile X Syndrome pathogenesis and for therapeutic development in repeat expansion disorders more broadly.

Performance runs through July 31, 2028, with place of performance in Aurora, Colorado. This is a Project Grant award, classified as assistance funding.

Abstract

Fragile x syndrome is one of the most common inherited causes of neurodevelopmental disorders and autism. Even though we have known about the genetic cause of fragile x syndrome, a trinucleotide repeat expansion at the FMR1 locus, for several decades, there are still no precision therapeutic interventions available. Model systems are inadequate in fully capturing the extent of cellular pathophysiology that occurs in the setting of the pathogenic repeat expansion, which causes hypermethylation of the locus and loss of FMR1 expression. Here we propose utilizing post-mortem human tissue from individuals with fragile x syndrome to study mechanisms and consequences of the repeat expansion directly in the human condition. Our team will study cell-type-specific gene expression in the fragile x syndrome human brain (aim 1), as well as phenomenon unique to the expansion itself that could be harnessed therapeutically- length and methylation mosaicism (aim 2). This project has the potential to be transformative for the understanding of the pathogenesis of fragile x syndrome, which has important implications for current and future therapeutic development, as well as repeat expansion disorders more broadly.