Current insights into the relationship between Ehlers-Danlos syndrome and gene expression

This narrative review synthesizes recent transcriptomic and mechanistic studies examining the relationship between gene expression and clinical manifestations in Ehlers-Danlos syndromes. Ehlers-Danlos syndromes (EDS) comprise a heterogeneous group of 13 heritable connective tissue disorders affecting approximately 1 in 5,000 individuals worldwide. Traditionally viewed as disorders of structural collagen defects, emerging evidence demonstrates that dysregulated gene expression and cellular signaling play crucial roles in disease pathogenesis. Using a structured synthesis of several transcriptomic and mechanistic studies, this review examines the relationship between gene expression patterns and clinical manifestations in the three most common EDS subtypes: classical, vascular, and hypermobile EDS. In cEDS, caused by mutations in COL5A1 or COL5A2, transcriptomic studies have revealed the downregulation of genes encoding periostin, osteopontin, and EDIL3, contributing to impaired wound healing and characteristic atrophic scarring. Vascular EDS, resulting from COL3A1 mutations, is characterized by reduced expression of fibrillin 2 and other collagen-processing enzymes, compromised autophagy and proteasomal degradation pathways, and vascular fragility. Hypermobile EDS, whose genetic basis remains elusive, demonstrates a complex pattern of extracellular matrix disorganization, enhanced matrix metalloproteinase activity, chronic inflammation, and aberrant fibroblast-to-myofibroblast transition. Across all subtypes, common themes included disrupted extracellular matrix homeostasis, cellular stress responses, and inflammation. Recent advances in transcriptomic, proteomic, and epigenetic profiling have transformed EDS research from a focus on structural defects to dynamic disorders in cellular signaling and homeostasis.