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Phelan PJ, Hall G, Wigfall D, et al. Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation. Clin Kidney J. 2015;8(5):538-42doi: 10.1093/ckj/sfv063.
Phelan, P. J., Hall, G., Wigfall, D., Foreman, J., Nagaraj, S., Malone, A. F., Winn, M. P., Howell, D. N., & Gbadegesin, R. (2015). Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation. Clinical kidney journal, 8(5), 538-42. https://doi.org/10.1093/ckj/sfv063
Phelan, Paul J, et al. "Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation." Clinical kidney journal vol. 8,5 (2015): 538-42. doi: https://doi.org/10.1093/ckj/sfv063
Phelan PJ, Hall G, Wigfall D, Foreman J, Nagaraj S, Malone AF, Winn MP, Howell DN, Gbadegesin R. Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation. Clin Kidney J. 2015 Oct;8(5):538-42. doi: 10.1093/ckj/sfv063. Epub 2015 Jul 20. PMID: 26413278; PMCID: PMC4581382.
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Clin Kidney J. 2015 Oct;8(5):538-42. doi: 10.1093/ckj/sfv063. Epub 2015 Jul 20.

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

Clinical kidney journal

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

Affiliations

  1. 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.
  2. Duke Molecular Physiology Institute , Duke University , Durham, NC , USA ; Division of Nephrology, Department of Medicine , Duke University Medical Center , Durham, NC , USA.
  3. Department of Nephrology , Royal Infirmary of Edinburgh, NHS Lothian , Edinburgh , UK.
  4. Department of Pathology , Duke University Medical Center , Durham, NC , USA.
  5. Duke Molecular Physiology Institute , Duke University , Durham, NC , USA ; Department of Pediatrics , Duke University Medical Center , Durham, NC , USA.

PMID: 26413278 PMCID: PMC4581382 DOI: 10.1093/ckj/sfv063

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.

Keywords: FSGS; NPHS2; familial; hereditary; nephrotic syndrome; proteinuria

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