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Original research
Circular RNA-based biomarkers in blood of patients with Fabry disease and related phenotypes
  1. Albina Nowak1,2,
  2. George Haddad3,
  3. Andreas D Kistler4,
  4. Stellor Nlandu-Khodo5,
  5. Felix Beuschlein1,
  6. Rudolf P Wüthrich3,
  7. Johan M Lorenzen3,
  8. Malte Kölling3,6
  1. 1 Department of Endocrinology, University Hospital Zurich, Zurich, Switzerland
  2. 2 Department of Internal Medicine, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland
  3. 3 Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
  4. 4 Department of Medicine, Frauenfeld Cantonal Hospital, Frauenfeld, Switzerland
  5. 5 Institute of Physiology, University of Zurich, Zurich, Switzerland
  6. 6 Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Berlin, Germany
  1. Correspondence to Professor Johan M Lorenzen, Department of Nephrology, University Hospital Zurich, Zurich 8091, Switzerland; Johan.Lorenzen{at}


Background Fabry disease is a rare X-linked lysosomal storage disease caused by mutations in the galactosidase α gene. Deficient activity of α-galactosidase A leads to glycosphingolipid accumulations in multiple organs. Circular RNAs represent strong regulators of gene expression. Their circular structure ensures high stability in blood. We hypothesised that blood-based circular RNA profiles improve phenotypic assignment and therapeutic monitoring of Fabry disease.

Methods A genome-wide circular RNA expression analysis was performed in blood of genetically diagnosed patients with Fabry disease (n=58), age-matched and sex-matched healthy volunteers (n=14) and disease control patients with acute kidney injury (n=109). Most highly dysregulated circular RNAs were validated by quantitative real-time PCR. Circular RNA biomarker sensitivity, specificity, predictive values and area under the curve (AUC) were determined. Linear regression analyses were conducted for validated circular RNA biomarkers and clinical patient characteristics.

Results A distinct circular RNA transcriptome signature identified patients with Fabry disease. Level of circular RNAs hsa_circ_0006853 (AUC=0.73), hsa_circ_0083766 (AUC=0.8) and hsa_circ_0002397 (AUC=0.8) distinguished patients with Fabry disease from both healthy controls and patients with acute kidney injury. Hsa_circ_0002397 was, furthermore, female-specifically expressed. Circular RNA level were significantly related to galactosidase α gene mutations, early symptoms, phenotypes, disease severities, specific therapies and long-term complications of Fabry disease.

Conclusion The discovery of circular RNA-based and Fabry disease–specific biomarkers may advance future diagnosis of Fabry disease and help to distinguish related phenotypes.

  • gene expression profiling
  • genetics
  • molecular biology
  • molecular diagnostic techniques
  • phenotype

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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  • JML and MK contributed equally.

  • Contributors AN, JML and MK designed the study. AN collected and monitored the patient data. JML provided the funding. MK performed the experiments. AN and MK analysed the data. AN, GH, ADK, SN-K, FB, RPW, JML and MK interpreted the data. AN and MK drafted the paper. AN, GH, ADK, SN-K, FB, RPW, JML and MK revised the paper. All authors approved the final version of the paper to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. AN, JML and MK are guarantors.

  • Funding JML received funding for this study from Shire (Takeda; grant number: IRR_CHE_001604). AN received lecturing honoraria and research support from Sanofi Genzyme, Shire (Takeda) and Amicus.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.