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

Phelan PJ, Hall G, Wigfall D, Foreman J, Nagaraj S, Malone AF, Winn MP, Howell DN, Gbadegesin R - Clin Kidney J (2015)

Bottom Line: 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.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.Individuals may present with early aggressive disease.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Family pedigrees with mutation chromatograms for the described families bearing variant R229Q plus pathogenic mutations in NPHS2. Squares represent males; circles represent females; solid shapes are affected individuals; crossed out shapes represent deceased family members.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4581382&req=5

SFV063F1: Family pedigrees with mutation chromatograms for the described families bearing variant R229Q plus pathogenic mutations in NPHS2. Squares represent males; circles represent females; solid shapes are affected individuals; crossed out shapes represent deceased family members.

Mentions: We found pathogenic mutations in 4/19 (21.1%) of the families studied, comprising an autosomal dominant WT1 mutation (c.1432+5G>A) in one family and NPHS2 mutations in three families. One of the mutations in NPHS2 is a homozygous frameshift mutation while the other two are compound heterozygous R229Q plus known pathogenic mutations. The phenotype of the four families with disease-causing mutations is shown in Table 1. The pedigrees in the two families with R229Q plus known pathogenic mutations are shown in Figure 1, while a detailed phenotypic description of these two families follows.Table 1.


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

Phelan PJ, Hall G, Wigfall D, Foreman J, Nagaraj S, Malone AF, Winn MP, Howell DN, Gbadegesin R - Clin Kidney J (2015)

Family pedigrees with mutation chromatograms for the described families bearing variant R229Q plus pathogenic mutations in NPHS2. Squares represent males; circles represent females; solid shapes are affected individuals; crossed out shapes represent deceased family members.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581382&req=5

SFV063F1: Family pedigrees with mutation chromatograms for the described families bearing variant R229Q plus pathogenic mutations in NPHS2. Squares represent males; circles represent females; solid shapes are affected individuals; crossed out shapes represent deceased family members.
Mentions: We found pathogenic mutations in 4/19 (21.1%) of the families studied, comprising an autosomal dominant WT1 mutation (c.1432+5G>A) in one family and NPHS2 mutations in three families. One of the mutations in NPHS2 is a homozygous frameshift mutation while the other two are compound heterozygous R229Q plus known pathogenic mutations. The phenotype of the four families with disease-causing mutations is shown in Table 1. The pedigrees in the two families with R229Q plus known pathogenic mutations are shown in Figure 1, while a detailed phenotypic description of these two families follows.Table 1.

Bottom Line: 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.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.Individuals may present with early aggressive disease.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus