Genomic Redundancy as a Driver of Chronicity in POTS and Long COVID: a Preliminary Study of Convergent Pathway Disruption

Author: Dr Graham Exelby October 2025.

A Reanalysis of: Exelby,G & Vittone,V.  DNA Mutations in POTS and Long COVID.2023 (redacted), with translational assistance from Dr Valerio Vittone.

Abstract

Background:

Dysautonomia, Postural Orthostatic Tachycardia Syndrome (POTS), ME/CFS, Long COVID, vaccine injury, and malignancy have traditionally been considered distinct conditions. However, accumulating evidence suggests they share molecular drivers.

Methods: 

We conducted SNP-based genomic analysis across six small but well-characterised patient cohorts (POTS, ME/CFS, Long COVID, vaccine reactors, hybrid virus–vaccine phenotypes, and malignancy within the other cohorts). Variants were curated into predefined pathways (innate immune activation, methylation/repair, mast-cell regulation, oxidative stress, kynurenine metabolism, COMT/hormonal balance, APOE/lipid handling, and structural preload failure). Clinical, biochemical, and imaging data were integrated with genomic findings. This study was designed to be hypothesis-generating, not hypothesis-testing.

Results: 

Eight recurrent pathway clusters were identified across cohorts, though with differing weightings. POTS was dominated by structural preload failure and mast-cell dysregulation; ME/CFS by methylation fragility, kynurenine excitotoxicity, and oxidative stress; Long COVID by multi-axis redundancy; vaccine reactors by innate immune, methylation, and mast-cell triad; hybrid virus–vaccine phenotypes by universal redundancy; and malignancy-linked cases by methylation/repair failure and inflammatory amplification.

Persistence appeared to correlate more with pathway redundancy than with initial trigger severity. APOE4 and COMT variants modified phenotype expression. Across all cohorts, the RAGE–TLR4–NLRP3–CCL2–STAT3 inflammatory amplifier loop was consistently observed.

Conclusion: 

In this preliminary study, these conditions appear not as discrete entities but as syndromic expressions of convergent pathway disruption. While limited by cohort size and absence of controls, the findings suggest that DNA pathway mapping may help define predictive phenotypes, stratify risk, and support pre-emptive interventions. This framework offers a potential step toward pathway-informed, anticipatory medicine.

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