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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.

SUBMITTER: Phelan PJ 

PROVIDER: S-EPMC4581382 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Phelan Paul J PJ   Hall Gentzon G   Wigfall Delbert D   Foreman John J   Nagaraj Shashi S   Malone Andrew F AF   Winn Michelle P MP   Howell David N DN   Gbadegesin Rasheed R  

Clinical kidney journal 20150720 5


<h4>Background</h4>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.<h4>Me  ...[more]

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