Birch et al. (2025)
- Authors: Camille L. Birch, Brandon M. Wilk, Manavalan Gajapathy, Shaurita D. Hutchins, Gurpreet Kaur, Donna M. Brown, Tarun K. K. Mamidi, Kathleen S. Hodgin, Alp Turgut, Jarred W. Younger, Elizabeth A. Worthey
- Institutes: Neuroinflammation, Pain and Fatigue Laboratory, University of Alabama at Birmingham, AL, USA, Center for Computational Genomics and Data Sciences, University of Alabama at Birmingham, AL, USA, HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
- Publisher: Journal of Translational Medicine
- Link: DOI
Summary
This study suggests that a significant subset of ME/CFS cases may be driven by rare, individual genetic mutations rather than common variants alone. By identifying pathogenic variants in nearly 40% of the participants, the research provides a biological basis for the disease’s heterogeneity and opens the door for precision diagnostics and personalized treatment strategies.
What was researched?
The researchers applied an individualized genomic and transcriptomic framework to investigate the role of rare, large-effect monogenic variations in patients with ME/CFS.
Why was it researched?
The study aimed to overcome the lack of universal biomarkers by testing the hypothesis that ME/CFS clinical heterogeneity is driven by distinct molecular disorders that converge on similar physiological pathways.
How was it researched?
The team conducted clinical-grade whole-genome sequencing on 31 participants from 25 families and performed RNA sequencing on a subset of 16 patients. They used machine-learning and expert triage to identify pathogenic variants and mapped these findings to specific biological pathways.
What has been found?
Pathogenic or likely pathogenic variants were found in 39% of affected individuals, specifically involving pathways like ATP 💊 generation, oxidative phosphorylation, and synaptic signaling. Despite high genetic diversity between patients, these individual mutations converged on core issues such as impaired energy production and reduced stress resilience.
Discussion
The results indicate that ME/CFS may be a collection of rare molecular disorders, explaining why large-scale studies often fail to find consistent markers. The precision approach successfully identified plausible modifiers that influence disease severity and individual symptoms.
Conclusion & Future Work
The study concludes that an individualized precision medicine framework can reveal molecular drivers previously obscured by patient heterogeneity. Larger validation studies are needed, but this approach likely represents the future of ME/CFS diagnostics and targeted intervention.