Beckwith-Wiedemann Syndrome (BWS, OMIM #130650) is a congenital epigenetic disorder in humans which affects approximately 1 in 10,340 children. The incidence is likely an underestimation as the condition is usually recognized based on observable phenotypes at birth. BWS children have up to a 28% risk of developing tumors and currently, only 80% of patients can be corroborated molecularly (epimutations/variants). It is unknown how the subtypes of this condition are molecularly similar/dissimilar globally, therefore there is a need to deeply characterize the syndrome at the molecular level. Here we characterize the methylome, transcriptome and chromatin configuration of 18 BWS individuals together with the animal model of the condition, the bovine large offspring syndrome (LOS). Sex specific comparisons are performed for a subset of the BWS patients and LOS. Given that this epigenetic overgrowth syndrome has been characterized as a loss-of-imprinting condition, parental allele-specific comparisons were performed using the bovine animal model. In general, the differentially methylated regions (DMRs) detected in BWS and LOS showed significant enrichment for CTCF binding sites. Altered chromosome compartments in BWS and LOS were positively correlated with gene expression changes, and the promoters of differentially expressed genes showed significant enrichment for DMRs, differential topologically associating domains, and differential A/B compartments in some comparisons of BWS subtypes and LOS. We show shared regions of dysregulation between BWS and LOS, including several HOX gene clusters, and also demonstrate that altered DNA methylation differs between the clinically epigenetically identified BWS patients and those identified as having DNA variants (i.e. CDKN1C microdeletion). Lastly, we highlight additional genes and genomic regions that have the potential to serve as targets for biomarker development to improve current molecular methodologies. In summary, our results suggest that genome-wide alternation of chromosome architecture, which is partially caused by DNA methylation changes, also contribute to the development of BWS and LOS.