Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation

Paul J. Phelan, Gentzon Hall, Delbert Wigfall, John Foreman, Shashi Nagaraj, Andrew F. Malone, Michelle P. Winn, David N. Howell, Rasheed Gbadegesin

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Background: Mutations in podocin (NPHS2) are the most common cause of childhood onset autosomal recessive steroidresistant nephrotic syndrome (SRNS). The disease is characterized by early-onset proteinuria, resistance to immunosuppressive therapy and rapid progression to end-stage renal disease. Compound heterozygous changes involving the podocin variant R229Q combined with another pathogenic mutation have been associated with a mild phenotype with disease onset often in adulthood. Methods: We screened 19 families with early-onset SRNS for mutations in NPHS2 and WT1 and identified four disease-causing mutations (three in NPHS2 and one in WT1) prior to planned whole-exome sequencing. Results: We describe two families with three individuals presenting in childhood who are compound heterozygous for R229Q and one other pathogenic NPHS2 mutation, either L327F or A297V. One child presented at age 4 years (A297V plus R229Q) and the other two at age 13 (L327F plus R229Q), one with steadily deteriorating renal function. Conclusions: These cases highlight the phenotypic variability associated with the NPHS2 R229Q variant plus pathogenic mutation. Individuals may present with early aggressive disease.

Original languageEnglish
Pages (from-to)538-542
Number of pages5
JournalClinical Kidney Journal
Issue number5
StatePublished - Oct 2015


  • FSGS
  • Familial
  • Hereditary
  • NPHS2
  • Nephrotic syndrome
  • Proteinuria


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