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      Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome

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      Clinical Journal of the American Society of Nephrology : CJASN

      American Society of Nephrology

      genetic renal disease, pediatric, molecular genetics, Child, Humans, Nephrosis, congenital, nephrotic syndrome, Exome, kidney transplantation, Mutation, Kidney Failure, Chronic, Renal Insufficiency, Chronic, Phenotype

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          Background and objectives

          Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.

          Design, setting, participants, & measurements

          Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.


          In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.


          Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.


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          Author and article information

          Clin J Am Soc Nephrol
          Clin J Am Soc Nephrol
          Clinical Journal of the American Society of Nephrology : CJASN
          American Society of Nephrology
          6 January 2018
          10 November 2017
          : 13
          : 1
          : 53-62
          Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
          Author notes

          J.K.W. and W.T. contributed equally to this work.

          Correspondence: Dr. Friedhelm Hildebrandt, Division of Nephrology, Department of Medicine, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115. Email: friedhelm.hildebrandt@ 123456childrens.harvard.edu
          PMC5753307 PMC5753307 5753307 04120417
          Copyright © 2018 by the American Society of Nephrology
          Page count
          Figures: 5, Tables: 1, Equations: 0, References: 33, Pages: 10
          Original Articles
          Custom metadata
          January 06, 2018


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