Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of severe chronic fatigue. — CFSMEATLAS
Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of severe chronic fatigue.
Oakley, Julia, Hill, Martin, Giess, Adam et al. · Journal of translational medicine · 2023 · DOI
Quick Summary
Researchers used advanced DNA sequencing technology to find a structural variant (a large rearrangement in genetic material) in the AKR1C gene region of a patient with severe, unexplained fatigue. This variant appears to alter how the body produces certain steroids and neurochemicals, potentially leading to reduced neuronal activity and widespread tissue dysfunction. The discovery suggests that genetic changes in this region may be a cause of severe chronic fatigue in some patients, and blood tests for specific steroid markers could help identify others with similar underlying issues.
Why It Matters
This study demonstrates that structural variants in complex genomic regions may account for previously undiagnosed cases of ME/CFS, particularly in patients with severe, treatment-resistant fatigue. The identification of specific steroid biomarkers provides a potential diagnostic tool to identify a patient subgroup that might benefit from targeted treatments. Understanding the mechanistic link between genetic variation and neurosteroid dysregulation opens new research and therapeutic directions for ME/CFS.
Observed Findings
A large DNA inversion in the AKR1C gene region was detected by long-read sequencing but could not be fully resolved by standard short-read sequencing methods.
The structural variant appears to increase AKR1C2 expression while decreasing AKR1C1 activity.
Serum steroid analysis revealed elevated inhibitory GABAergic neurosteroids and impaired progesterone metabolism in the patient.
Standard bioinformatics tools were confounded by the high homology in this region; accurate variant characterization required manual visual inspection combined with automated analysis.
Inferred Conclusions
Structural variants in tandem gene array regions may account for cases of severe chronic fatigue that lack clear genetic diagnoses using conventional sequencing approaches.
AKR1C gene rearrangements resulting in altered steroid metabolism may represent a novel disease etiology in a subset of ME/CFS patients.
Serum steroid biomarkers (particularly GABAergic neurosteroid levels and progesterone metabolites) could be used to identify and stratify patients with this genetic subtype for targeted investigation and treatment.
Remaining Questions
What is the prevalence of AKR1C inversion variants in the broader ME/CFS patient population?
Do other patients with ME/CFS and similar steroid metabolite profiles carry the same or different structural variants in this genomic region?
What This Study Does Not Prove
This single case study does not prove that AKR1C variants cause ME/CFS in the general patient population, nor does it establish the prevalence of this variant among ME/CFS patients. The study cannot determine whether the observed steroid abnormalities are causative of fatigue or merely associated, and findings from one patient may not generalize to other patients with ME/CFS. Further validation in larger, prospective cohorts is required before any diagnostic or therapeutic claims can be substantiated.