title: Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation.
abstract: BACKGROUND
  Mutations in podocin (NPHS2) are the most common cause of childhood onset autosomal recessive steroid-resistant 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.
authors.affiliation: Duke Molecular Physiology Institute , Duke University , Durham, NC , USA ; Division of Nephrology, Department of Medicine , Duke University Medical Center , Durham, NC , USA ; Department of Nephrology , Royal Infirmary of Edinburgh, NHS Lothian , Edinburgh , UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Phelan
authors.affiliation: Duke Molecular Physiology Institute , Duke University , Durham, NC , USA ; Division of Nephrology, Department of Medicine , Duke University Medical Center , Durham, NC , USA.
authors.forename: Gentzon
authors.initials: G
authors.lastname: Hall
authors.affiliation: Department of Nephrology , Royal Infirmary of Edinburgh, NHS Lothian , Edinburgh , UK.
authors.forename: Delbert
authors.initials: D
authors.lastname: Wigfall
authors.affiliation: Department of Nephrology , Royal Infirmary of Edinburgh, NHS Lothian , Edinburgh , UK.
authors.forename: John
authors.initials: J
authors.lastname: Foreman
authors.affiliation: Department of Nephrology , Royal Infirmary of Edinburgh, NHS Lothian , Edinburgh , UK.
authors.forename: Shashi
authors.initials: S
authors.lastname: Nagaraj
authors.affiliation: Duke Molecular Physiology Institute , Duke University , Durham, NC , USA ; Division of Nephrology, Department of Medicine , Duke University Medical Center , Durham, NC , USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Malone
authors.affiliation: Duke Molecular Physiology Institute , Duke University , Durham, NC , USA ; Division of Nephrology, Department of Medicine , Duke University Medical Center , Durham, NC , USA.
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Winn
authors.affiliation: Department of Pathology , Duke University Medical Center , Durham, NC , USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Howell
authors.affiliation: Duke Molecular Physiology Institute , Duke University , Durham, NC , USA ; Department of Pediatrics , Duke University Medical Center , Durham, NC , USA.
authors.forename: Rasheed
authors.initials: R
authors.lastname: Gbadegesin
keywords: FSGS; NPHS2; familial; hereditary; nephrotic syndrome; proteinuria