Stefanie Weber1, Anja K Büscher1, Henning Hagmann2, Max C Liebau2,3, Christian Heberle4, Michael Ludwig5, Sabine Rath4, Martin Alberer6, Antje Beissert7, Martin Zenker8, Peter F Hoyer1, Martin Konrad9, Hanns-Georg Klein4, Julia Hoefele10. 1. Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany. 2. Renal Division, Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany. 3. Department of Pediatrics, University Hospital of Cologne, Cologne, Germany. 4. Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany. 5. Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. 6. Department of Infectious Diseases and Tropical Medicine, Ludwig-Maximilians University, Munich, Germany. 7. Pediatric Nephrology, University Children's Hospital, Würzburg, Germany. 8. Institute of Human Genetics, University Hospital, Magdeburg, Germany. 9. University Children's Hospital, Münster, Germany. 10. Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany. jhoefele@gmx.de.
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.
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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