title: A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.
abstract: Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Carolin E
authors.initials: CE
authors.lastname: Sadowski
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Svjetlana
authors.initials: S
authors.lastname: Lovric
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Shazia
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Werner L
authors.initials: WL
authors.lastname: Pabst
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Susanne
authors.initials: S
authors.lastname: Engelmann
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
authors.forename: Virginia
authors.initials: V
authors.lastname: Vega-Warner
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Humphrey
authors.initials: H
authors.lastname: Fang
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Somers
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Weizhen
authors.initials: W
authors.lastname: Tan
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Shirlee
authors.initials: S
authors.lastname: Shril
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Inès
authors.initials: I
authors.lastname: Fessi
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Institute of Child Health, University College London, London, United Kingdom;
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.affiliation: Pediatric Nephrology Unit, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia;
authors.forename: Sherif
authors.initials: S
authors.lastname: El-Desoky
authors.affiliation: Pediatric Nephrology Unit, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia;
authors.forename: Jameela A
authors.initials: JA
authors.lastname: Kari
authors.affiliation: Department of Human Genetics, Otto von Guericke University, Magdeburg, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: Department of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Kemper
authors.affiliation: Department of Pediatric Nephrology, Medical Faculty of the Charité, Berlin, Germany;
authors.forename: Dominik
authors.initials: D
authors.lastname: Mueller
authors.affiliation: The Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt;
authors.forename: Hanan M
authors.initials: HM
authors.lastname: Fathy
authors.affiliation: Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt; Egyptian Group for Orphan Renal Diseases, Cairo, Egypt; and.
authors.forename: Neveen A
authors.initials: NA
authors.lastname: Soliman
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland friedhelm.hildebrandt@childrens.harvard.edu.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D016162:Genes, Wilms Tumor; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein
keywords: FSGS; SRNS; genetic disease; kidney failure; nephrosis; steroid-resistant nephrotic syndrome