BackgroundAbnormal DNA methylation is thought to contribute to the onset and progression of systemic sclerosis. Currently, the most comprehensive assay for profiling DNA methylation is whole-genome bisulfite sequencing (WGBS), but its precision depends on read depth and it may be subject to sequencing errors.SOMNiBUS, a method forregionalanalysis, attempts to overcome some of these limitations. UsingSOMNiBUS,we re-analyzed WGBS data previously analyzed usingbumphunter, an approach that initially fitssingleCpG associations, to contrast DNA methylation estimates by both methods.MethodsPurified CD4+ T lymphocytes of 9 SSc and 4 control females were sequenced using WGBS. We separated the resulting sequencing data into regions with dense CpG data, and differentially methylated regions (DMRs) were inferred with theSOMNiBUSregion-level test, adjusted for age. Pathway enrichment analysis was performed with ingenuity pathway analysis (IPA). We compared the results obtained bySOMNiBUSandbumphunter.ResultsOf 8268 CpG regions of ≥ 60 CpGs eligible for analysis withSOMNiBUS, we identified 131 DMRs and 125 differentially methylated genes (DMGs;p-values less than Bonferroni-corrected threshold of 6.05–06 controlling family-wise error rate at 0.05; 1.6% of the regions). In comparison,bumphunteridentified 821,929 CpG regions, 599 DMRs (of which none had ≥ 60 CpGs) and 340 DMGs (q-value of 0.05; 0.04% of all regions). The top ranked gene identified bySOMNiBUSwasFLT4, a lymphangiogenic orchestrator, and the top ranked gene on chromosome X wasCHST7, known to catalyze the sulfation of glycosaminoglycans in the extracellular matrix. The top networks identified byIPAincluded connective tissue disorders.ConclusionsSOMNiBUSis a complementary method of analyzing WGBS data that enhances biological insights into SSc and provides novel avenues of investigation into its pathogenesis.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13148-023-01513-w.