RNA sequencing to define pathogenetic mechanisms involved in hypermobile Ehlers-Danlos syndrome and Hypermobility Spectrum Disorders

Background: Hypermobile Ehlers-Danlos syndrome (hEDS), the most common form of EDS, remains without a defined molecular basis and its diagnosis relies on a set of recently defined clinical manifestations. Patients with symptomatic joint hypermobility not fulfilling these diagnostic criteria are classified as hypermobility spectrum disorders (HSD). Our previous transcriptome and protein findings demonstrated that hEDS and HSD fibroblasts share the dysregulated expression of some matrisome- and inflammatory/pain-related genes and exhibit a pro-inflammatory myofibroblast-like phenotype. Research objectives and study design: We plan to sequence the transcriptome (RNA-seq) of dermal fibroblasts from a large cohort of hEDS, HSD patients and healthy subjects to identify common and/or distinctive expression signatures and perturbed biological processes. RNA-seq data analysis will be performed using a set of integrated web applications for differential gene expression and pathway analysis. Quantitative PCR will be carried out to validate the most relevant differentially expressed genes in both EDS cell types. Anticipated outcomes: The proposed study will shed light on the complex gene network and dysregulated processes involved in the hEDS and HSD pathobiology, also providing evidence on the hypothesis that both conditions might be either part of a phenotypic continuum or represent distinct clinical entities with a different etiology. Since we are currently involved in the definition of proteomic signatures in hEDS and HSD cells, the integration of transcriptome and proteome profiling will expand the biological knowledge of the complex pathophysiology underlying both conditions. The disclosure of these biological signatures and dysregulated pathways may also impact on the forthcoming hEDS genetic study by supporting the interpretation of candidate genomic variants and potentially elucidating their functional effects on key processes involved in the disease pathogenesis..