Background: The Repeat Expansion Diseases are a group of 40+ human genetic disorders that are caused by expansions of a disease-specific tandem repeat or microsatellite. In a subset of these diseases, the expanded alleles become epigenetically silenced via a process we are still trying to understand. Silencing results in a deficiency of the protein product of the affected gene that is the proximal cause of disease pathology. In the case of Fragile X syndrome (FXS), the most common heritable cause of intellectual disability and autism, the silenced gene is FMR1 and as a result the protein product of FMR1, FMRP, is severely reduced. FMRP is involved in, amongst other things, the regulation of translation in the brain, as well as insulin signaling and glucose metabolism. In the case of FRDA, the affected gene is FXN and its protein product is frataxin, a mitochondrial protein thought to be important in iron-cluster biogenesis. In the case of GDPAG, gene silencing affects the Glutaminase 1 (GLS1) gene and results in a deficiency of glutamate, a critical neurotransmitter in the brain. In contrast to the gene silencing that is seen in the case of very large repeat tracts in the FMR1 gene, carriers of smaller alleles show FMR1 hyperexpression. This hyperexpression is associated with a form of adult onset neurodegeneration, Fragile X-associated tremor/ataxia syndrome (FXTAS), and a form of female infertility known as FX-associated primary ovarian insufficiency (FXPOI). Progress report: In this reporting period we generated a new cell model for studying the consequences of repeat expansion in the Fragile X-related disorders (Gazy et. al., 2020). This cell model recapitulates, not only the tendency of the repeats to expand, but manifests some of the abnormalities seen in individuals with FXTAS including elevated FMR1 transcription and altered mitochondrial copy number. Interestingly, the elevated level of transcription was oxygen-sensitive. This may provide clues to the molecular basis of the altered transcription, a phenomenon that is thought to contribute to disease pathology. We have also extended our studies on the molecular events associated with gene silencing and reactivation in FXS, to show that a subset of small molecule inhibitors of histone methylation can significantly delay the resilencing of the FM allele that is seen after chemical gene reactivation (Kumari et. al., 2020; Kumari and Usdin, 2020). This suggests ways to approach an epigenetic treatment of these disorders. We are also continuing our work on identifying new Repeat Expansion Diseases and providing improved tools for the diagnosis of these diseases (Hayward et. al., 2019).