Multi-Omic Integration of the miRNome and Transcriptome in Dermal Fibroblasts from Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Identifies Convergent Candidate miRNA-mRNA Regulatory Networks Linking Extracellular Matrix Rem

Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically defined connective tissue conditions lacking molecular biomarkers. We tested whether their transcriptomic convergence extends to miRNA-mediated post-transcriptional regulation. miRNome sequencing was performed in cultured dermal fibroblasts from 12 individuals with hEDS, 12 with HSD, and 24 controls. Twenty-five differentially expressed miRNAs (DE-miRNAs) were assessed by qPCR in pooled discovery material and an independent pooled cohort. No miRNA met differential-expression threshold in the direct hEDS versus HSD comparison, whereas pooled hEDS/HSD analysis identified 88 DE-miRNAs versus controls (42 upregulated, 46 downregulated). qPCR supported cross-platform and pooled group-level concordance but did not assess interindividual validation. Experimentally supported targets of upregulated DE-miRNAs overlapped 388 downregulated genes significantly more than expected by chance; these genes converged on extracellular matrix remodeling, TGF-β/BMP, Wnt/Hippo, focal adhesion, and cytoskeletal programs. The 27-gene inverse overlap for downregulated DE-miRNAs did not exceed chance expectation but included literature-supported chemokine and matrix-degradative candidates. These hypothesis-generating findings define a shared group-level fibroblast miRNA pattern and prioritize candidate regulatory axes. Because the study used cultured cells and pooled qPCR without paired biofluids, longitudinal sampling, or phenotype correlations, its in vivo and biomarker implications remain preliminary.