Bryant-Li-Bhoj syndrome (BLBS) is a mixed neurodevelopmental-neurodegenerative syndrome characterized by developmental delay, intellectual disability, and multiple congenital anomalies. BLBS is caused by germline variants in H3-3A and H3-3B, which encode histone 3.3 (H3.3). There are 70 known BLBS causative variants which span both genes. To further understand the cellular effects of this broad array of variants, we first investigated in BLBS patient-derived dermal fibroblasts the proliferative phenotype of BLBS in which cells senesce prematurely after a phase of hyperproliferation. We found that while the premature senescence phenotype was consistent across variants, the cause of senescence appears to diverge between variants. Some variants, particularly those which affect H3.3 chaperone binding, result in shortened telomeres, while others exhibit increased DNA damage. We then explored the transcriptional profile of BLBS dermal fibroblasts and found that the most dysregulated pathways across variants are developmental pathways, including neurodevelopmental pathways. We found that, while many genes are differentially regulated in only cells with one causative variant, these variant-specific dysregulated genes converge on developmental processes, cell cycle regulation, and metabolic pathways. This aberrant gene expression may be due to several disrupted regulatory mechanisms, including transcription factor binding, chromatin accessibility, histone post-translational modifications, and DNA methylation. To evaluate DNA methylation as a potential biomarker for BLBS diagnosis, we used a whole-genome methylation microarray to evaluate the DNA methylation in dermal fibroblasts and whole blood. We found that we are unable to identify a consistent DNA methylation profile in BLBS fibroblasts or blood, suggesting that DNA methylation may not be an effective biomarker for BLBS and that gene dysregulation in BLBS may not be primarily mediated by DNA methylation. This analysis of some of the most fundamental cellular phenotypes of BLBS, proliferation, gene expression, and DNA methylation, offer new insight into the mechanisms of BLBS and the convergence of its many causative variants. This thesis work provides a new understanding of BLBS at the cellular level, thus building a foundation for future studies on key cellular pathways that are dysregulated in BLBS.