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Dealing with the incidental finding of secondary variants by the example of SRNS patients undergoing targeted next-generation sequencing

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Abstract

Background

Steroid-resistant nephrotic syndrome (SRNS) is a severe cause of progressive renal disease. Genetic forms of SRNS can present with autosomal recessive or autosomal dominant inheritance. Recent studies have identified mutations in multiple podocyte genes responsible for SRNS. Improved sequencing methods (next-generation sequencing, NGS) now promise rapid mutational testing of SRNS genes.

Methods

In the present study, a simultaneous screening of ten SRNS genes in 37 SRNS patients was performed by NGS.

Results

In 38 % of the patients, causative mutations in one SRNS gene were found. In 22 % of the patients, in addition to these mutations, a secondary variant in a different gene was identified.

Conclusions

This high incidence of accumulating sequence variants was unexpected but, although they might have modifier effects, the pathogenic potential of these additional sequence variants seems unclear so far. The example of molecular diagnostics by NGS in SRNS patients shows that these new sequencing technologies might provide further insight into molecular pathogenicity in genetic disorders but will also generate results, which will be difficult to interpret and complicate genetic counseling. Although NGS promises more frequent identification of disease-causing mutations, the identification of causative mutations, the interpretation of incidental findings and possible pitfalls might pose problems, which hopefully will decrease by further experience and elucidation of molecular interactions.

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Acknowledgments

We thank the patients and their families for participation in this study. JH, AKB, MCL, and SW received financial support by the German Society of Pediatric Nephrology.

Conflict of interest

The author(s) declare that they have no competing interests.

Ethical approval

The study was approved by the ethics committee of the University of Duisburg-Essen and is in adherence to the Declaration of Helsinki.

Informed consent

Informed consent was obtained from the patients or the patients’ guardians.

Author information

Authors and Affiliations

  1. Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany

    Stefanie Weber, Anja K. Büscher & Peter F. Hoyer

  2. Renal Division, Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

    Henning Hagmann & Max C. Liebau

  3. Department of Pediatrics, University Hospital of Cologne, Cologne, Germany

    Max C. Liebau

  4. Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany

    Christian Heberle, Sabine Rath, Hanns-Georg Klein & Julia Hoefele

  5. Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany

    Michael Ludwig

  6. Department of Infectious Diseases and Tropical Medicine, Ludwig-Maximilians University, Munich, Germany

    Martin Alberer

  7. Pediatric Nephrology, University Children’s Hospital, Würzburg, Germany

    Antje Beissert

  8. Institute of Human Genetics, University Hospital, Magdeburg, Germany

    Martin Zenker

  9. University Children’s Hospital, Münster, Germany

    Martin Konrad

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  1. Stefanie Weber
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Weber, S., Büscher, A.K., Hagmann, H. et al. Dealing with the incidental finding of secondary variants by the example of SRNS patients undergoing targeted next-generation sequencing. Pediatr Nephrol 31, 73–81 (2016). https://doi.org/10.1007/s00467-015-3167-6

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