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Despite its significant impact on quality of life, ME\/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME\/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch\n                    <jats:sup>\u00ae<\/jats:sup>\n                    , that employs an algorithm-based CCs analysis. Using EpiSwitch\n                    <jats:sup>\u00ae<\/jats:sup>\n                    technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1\/PD-L1 antagonists, with 85% accuracy. In this Retrospective case\/control study (EPI-ME,\n                    <jats:italic>Epigenetic Profiling Investigation in Myalgic Encephalomyelitis)<\/jats:italic>\n                    , we used whole blood samples retrospectively collected from\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200947 patients with severe ME\/CFS and\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200961 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME\/CFS diagnosis. We identified a 200-marker model for ME\/CFS diagnosis (Episwitch\n                    <jats:sup>\u00ae<\/jats:sup>\n                    CFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME\/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME\/CFS, including interleukins, TNF\u03b1, neuroinflammatory pathways, toll-like receptor signalling and JAK\/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME\/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.\n                  <\/jats:p>","DOI":"10.1186\/s12967-025-07203-w","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T22:02:24Z","timestamp":1759874544000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS) using EpiSwitch\u00ae 3-dimensional genomic regulatory immuno-genetic profiling"],"prefix":"10.1186","volume":"23","author":[{"given":"Ewan","family":"Hunter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Alshaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Bundock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cicely","family":"Weston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shekinah","family":"Bautista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abel","family":"Gebregzabhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anya","family":"Virdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Croxford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Dring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Vugrinec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Kingdon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Dowrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayne","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Akoulitchev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1074-9261","authenticated-orcid":false,"given":"Dmitri","family":"Pchejetski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"issue":"1","key":"7203_CR1","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1186\/s12916-023-02893-9","volume":"21","author":"R Maksoud","year":"2023","unstructured":"Maksoud R, Magawa C, Eaton-Fitch N, Thapaliya K, Marshall-Gradisnik S. 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