We hope that our identification of clinically correlated mosaic H3K9me3 BREACH genes will inspire new insights into pathophysiology and therapeutic strategies in FXS! 14/fin

For some speculation as to why these mosaic BREACH genes are associated with greater disease severity? Both SLITRK4 and KHDRBS2 importantly regulate synaptogenesis, so maybe higher levels of these genes contribute the hyperexcitability hypothesized to underly some FXS symptoms. 13/n

We are stronger together, and attacks on individual parts of our ecosystem will weak us all. academyhealth.org/blog/2025-03... 12/n

Especially important to highlight are data made accessible by others funded by federal sources. The sustained commitment to funding research compounds and enables synergies as my work here would have been weaker without drawing on the independent datasets from the Richter and Kriegstein labs. 11/n

Check out the preprint for the FXS patient brain analyses where we recapitulate the core findings. Thank you to the wonderful people who contributed data: Thomas, Chuanbin, Ji Hun, & Linda. Jenn for her unwavering support. Thank you to the funding that have enabled me to conduct this work! 10/n

To summarize:
H3K9me3 BREACHes are a source of epigenomic variation that explain the gene repression across individuals with FXS.
Mosaic BREACH genes are enriched for associations with ASD.
Mosaic BREACH gene expression are clinical severity correlates in individuals with FXS and ASD.
9/n

We validate our findings with brain data from individuals with autism spectrum disorder (ASD) published by the Kriegstein lab (PMID: 31097668). We find that KHDRBS2 & SLITRK4 mRNA in brain are associated with worse symptoms in ASD, unlike top non-BREACH genes which showed no correlation. 8/n

We asked which genes contributed power alongside FMRP to predicting ABC scores. We find that mosaic BREACH genes add predictive value to FMRP levels for correlates of FXS severity. KHDRBS2 & SLITRK4 mRNA is associated with worse symptoms, unlike FMRP and top non-BREACH genes. 7/n

Upon identifying mosaic BREACH genes, we wanted to assess if they were clinical correlates to FXS severity. So, we turned to a dataset from the Richter lab (PMID: 37364131) which had gene expression and FMRP levels in blood samples and measurement of adaptive functioning, ABC score. 6/n

When we quantify the variability of H3K9me3 at BREACHes, we find that the variation in gene repression is correlated with the mosaicism of H3K9me3 across FXS patients. The genes with the greatest heterogeneity across FXS patients are enriched for associations with autism spectrum disorder genes. 5/n

By using FXS patient derived iPSCs differentiated to neural progenitor cells (NPCs), we find wide variability of FXS H3K9me3 BREACHes across FXS patients. 4/n

Landmark studies in the 90s demonstrated that epigenetic variation of DNA methylation at FMR1 as an important source of variation that help explains the variation in disease severity. So, we asked if H3K9me3 BREACHes vary across FXS patient epigenomes. 3/n

Inspired by classic work in FXS mosaicism of DNA methylation at FMR1, we find that across FXS patients, H3K9me3 heterochromatin varies and heterogeneously represses synaptic genes associated with neurodevelopmental disorders and correlated with disease severity. 2/n
www.biorxiv.org/content/10.1...