Basic ResearchA Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic SyndromeSadowski, Carolin E.*; Lovric, Svjetlana*; Ashraf, Shazia*; Pabst, Werner L.*; Gee, Heon Yung*; Kohl, Stefan*; Engelmann, Susanne*; Vega-Warner, Virginia†; Fang, Humphrey*; Halbritter, Jan*; Somers, Michael J.*; Tan, Weizhen*; Shril, Shirlee*; Fessi, Inès*; Lifton, Richard P.‡; Bockenhauer, Detlef§; El-Desoky, Sherif‖; Kari, Jameela A.‖; Zenker, Martin¶; Kemper, Markus J.**; Mueller, Dominik††; Fathy, Hanan M.‡‡; Soliman, Neveen A.§§,‖‖; Hildebrandt, Friedhelm*,¶¶ the SRNS Study Group Author Information *Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts; †Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan; ‡Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut; §Institute of Child Health, University College London, London, United Kingdom; ‖Pediatric Nephrology Unit, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia; ¶Department of Human Genetics, Otto von Guericke University, Magdeburg, Germany; **Department of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg, Germany; ††Department of Pediatric Nephrology, Medical Faculty of the Charité, Berlin, Germany; ‡‡The Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt; §§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 ¶¶Howard Hughes Medical Institute, Chevy Chase, Maryland C.E.S. and S.L. contributed equally to this work. Correspondence: Dr. Friedhelm Hildebrandt, Howard Hughes Medical Institute, Division of Nephrology, Department of Medicine, Boston Children’s Hospital, 300 Longwood Avenue, Enders 561, Boston, MA 02115. Email: [email protected] Received May 19, 2014 Accepted September 10, 2014 Journal of the American Society of Nephrology 26(6):p 1279-1289, June 2015. | DOI: 10.1681/ASN.2014050489 Buy Metrics 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. Copyright © 2015 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.