title: Dealing with the incidental finding of secondary variants by the example of SRNS patients undergoing targeted next-generation sequencing.
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.
authors.affiliation: Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
authors.affiliation: Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Büscher
authors.affiliation: Renal Division, Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Hagmann
authors.affiliation: Renal Division, Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany.|Department of Pediatrics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Max C
authors.initials: MC
authors.lastname: Liebau
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Heberle
authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rath
authors.affiliation: Department of Infectious Diseases and Tropical Medicine, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Alberer
authors.affiliation: Pediatric Nephrology, University Children's Hospital, Würzburg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Beissert
authors.affiliation: Institute of Human Genetics, University Hospital, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Hoyer
authors.affiliation: University Children's Hospital, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany.
authors.forename: Hanns-Georg
authors.initials: HG
authors.lastname: Klein
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany. jhoefele@gmx.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoefele
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D033162:Incidental Findings; D007223:Infant; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D055815:Young Adult
chemical_list: D005819:Genetic Markers
keywords: Focal segmental glomerulosclerosis; Incidental findings; Nephrotic syndrome; SRNS; Secondary variants