Whole Exome Sequencing of Patients With Steroid-Resistant Nephrotic Syndrome

Clin J Am Soc Nephrol. 2018 Jan 6;13(1):53-62. doi: 10.2215/CJN.04120417. Epub 2017 Nov 10.

Abstract

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.

Results: 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.

Conclusions: 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.

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

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Child
  • Child, Preschool
  • DNA Mutational Analysis / methods*
  • Female
  • Genetic Association Studies
  • Genetic Markers*
  • Genetic Predisposition to Disease
  • Heredity
  • Humans
  • Infant
  • Male
  • Mutation Rate
  • Mutation*
  • Nephrotic Syndrome / congenital*
  • Nephrotic Syndrome / diagnosis
  • Nephrotic Syndrome / epidemiology
  • Nephrotic Syndrome / genetics
  • Nephrotic Syndrome / therapy
  • Pedigree
  • Phenotype
  • Predictive Value of Tests
  • Prognosis
  • Whole Exome Sequencing*
  • Young Adult

Substances

  • Genetic Markers

Supplementary concepts

  • Nephrotic syndrome, idiopathic, steroid-resistant