Revealing the etiology of hypermobile ehlers-danlos syndrome: A method using skin organoids and epigenetics

Summary: Abstract Body: Introduction: Ehlers-Danlos Syndrome (EDS) is a group of inherited connective tissue disorders primarily characterized by musculoskeletal manifestations, accompanied by a range of complex comorbidities that severely impact quality of life. The most common form of EDS, hypermobile Ehlers-Danlos Syndrome (hEDS), currently has no known genetic cause and relies on a clinical diagnosis. Estimates of the prevalence of hEDS are around 1 in 3,100, which is likely an underestimate as many patients are without a diagnosis. The complexity of hEDS, stemming from its variable symptom presentation, suggests that its genetic underpinnings are more complex than previously believed, likely consisting of multiple subgroups with individual etiologies. hEDS pathology is likely influenced by polygenic and/or epigenetic factors, which further complicates the characterization of the disorder. Methods: To address this, we have developed a method to investigate DNA methylation changes in skin tissues of hEDS patients, a commonly affected organ of hEDS patients. This method generates skin organoid derived fibroblasts (iFs) from induced pluripotent stem cells (iPSCs) of hEDS patients. During the process of reprogramming cells into iPCS, most of DNA methylation marks are lost. Disease associated marks can be reestablished during differentiation of iFs without background noise of environmental factors, known as episignatures. Results: These hEDS specific- episignatures were identified using Oxford Nanopore Technology (ONT), simultaneously identifying genetic and epigenetic perturbations in hEDS iFs. Differentially methylated regions in hEDS patients compared to both unaffected family members and unrelated controls were evaluated. Episignatures in these genomic regions in hEDS patients provide important insights into the etiology of disorder and allow for further investigations of the molecular underpinnings of hEDS. Megan Kraus¹, Ellen Elias², Melissa Haendel³, Ganna Bilousova¹ 1. Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States. 2. Children's Hospital Colorado, Aurora, CO, United States. 3. Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics