Proximity extension assay-based serum proteomic profiling identifies shared protein signatures in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders

Background: Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are prevalent conditions characterized by symptomatic joint hypermobility and a substantial public health burden, for which no causal treatment is currently available. In the absence of a defined molecular basis or validated diagnostic biomarkers, diagnosis of hEDS relies solely on the 2017 clinical criteria, with individuals who do not meet these criteria classified as HSD. Although currently categorized as distinct entities, the biological relationship between hEDS and HSD remains a subject of active debate within the scientific community. Methods: We performed targeted serum proteomic profiling using the proximity extension assay technology, quantifying 458 proteins in large cohorts of hEDS (n = 88) and HSD (n = 88) patients, alongside healthy controls (n = 176). Results: Compared to controls, 54 proteins were differentially expressed in hEDS patients and 49 in HSD patients. No statistically significant differences were observed between hEDS and HSD groups. When the combined patient cohort was analyzed, 69 proteins showed differential expression relative to controls. The proteins were distributed across the predefined PEA panels, which include proteins involved in inflammatory, cardiometabolic, neurological, organ damage, and developmental processes. Conclusions: This targeted serum proteomic analysis identified overlapping protein expression changes in hEDS and HSD relative to controls, while revealing no detectable differences between the two conditions. These findings suggest the presence of shared molecular features across the hEDS/HSD spectrum and identify a set of candidate circulating proteins that warrant further investigation and independent validation in larger, well-characterized cohorts.