Fragile X Premutations- Mechanisms and Modifiers Fragile X-associated disorders are a heterogeneous group of conditions arising from alterations in the size, content, and epigenetic state of a polymorphic CGG repeat within the FMR1 gene. Described as the first repeat expansion disorder nearly 30 years ago, FMR1 CGG repeat expansions are both an important cause of neurological, reproductive and neurodevelopmental disease as well as an archetype for understanding repeat expansions and the mechanisms by which they elicit dysfunction. Work over past decades delineated the native functions of the fragile X protein, FMRP, and the consequences of its loss and the explored toxic gain-of function mechanisms (RNA-mediated toxicity via protein sequestration, and protein mediated toxicity from Repeat associated non-AUG (RAN) translation) elicited by transcribed CGG repeats. Despite these efforts, we still lack effective therapies for any of the cardinal Fragile X- associated disorders. Here we propose a paradigm shift in our approach to FX associated disorders. Rather than focusing solely on specific diseases (Fragile X Syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI)), the Center structure enables us to directly engage the mechanistic cross-talk between conditions and between the FMR1 locus and related repeat expansion disorders. Our central hypothesis is that a deeper understanding of genetic factors which underlie clinical disease onset and penetrance in premutation associated disorders and an exploration of native CGG repeat functions will reveal novel insights into both how repeats cause disease and how they might be targeted therapeutically. Led by a multidisciplinary team featuring many leaders in the Fragile X field, we will address this hypothesis in three cohesive projects all focused on premutation disorders by using data-driven genomic and bioinformatics approaches coupled with emerging tools and integrative model systems. By pooling our substantial data, expertise and resources, we will pursue a deeper understanding of FX premutation pathogenic mechanisms and define a series of robust and viable targets for therapeutic development across Fragile X-associated disorders.