Genotype-phenotype associations in WT1 glomerulopathy

Beata S. Lipska, Bruno Ranchin, Paraskevas Iatropoulos, Jutta Gellermann, Anette Melk, Fatih Ozaltin, Gianluca Caridi, Tomas Seeman, K. Tory, Augustina Jankauskiene, Aleksandra Zurowska, Maria Szczepanska, Anna Wasilewska, Jerome Harambat, Agnes Trautmann, Amira Peco-Antic, Halina Borzecka, Anna Moczulska, Bassam Saeed, Radovan BogdanovicMukaddes Kalyoncu, Eva Simkova, Ozlem Erdogan, Kristina Vrljicak, Ana Teixeira, Marta Azocar, Franz Schaefer

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype-phenotype correlations of 61 patients with WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype-phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.

Original languageEnglish
Pages (from-to)1169-1178
Number of pages10
JournalKidney International
Volume85
Issue number5
DOIs
Publication statusPublished - 2014

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Nephrotic Syndrome
Genetic Association Studies
Steroids
Focal Segmental Glomerulosclerosis
Wilms Tumor
Mutation
Chronic Kidney Failure
Urogenital Abnormalities
Gonadoblastoma
Chronic Renal Insufficiency
Age of Onset
Disease Progression
Hypertension
Phenotype
Kidney
Biopsy
DNA
Genes

Keywords

  • Denys-Drash syndrome
  • Diffuse mesangial sclerosis
  • Focal segmental glomerulosclerosis
  • Frasier syndrome
  • Steroid-resistant nephrotic syndrome
  • WT1

ASJC Scopus subject areas

  • Nephrology
  • Medicine(all)

Cite this

Lipska, B. S., Ranchin, B., Iatropoulos, P., Gellermann, J., Melk, A., Ozaltin, F., ... Schaefer, F. (2014). Genotype-phenotype associations in WT1 glomerulopathy. Kidney International, 85(5), 1169-1178. https://doi.org/10.1038/ki.2013.519

Genotype-phenotype associations in WT1 glomerulopathy. / Lipska, Beata S.; Ranchin, Bruno; Iatropoulos, Paraskevas; Gellermann, Jutta; Melk, Anette; Ozaltin, Fatih; Caridi, Gianluca; Seeman, Tomas; Tory, K.; Jankauskiene, Augustina; Zurowska, Aleksandra; Szczepanska, Maria; Wasilewska, Anna; Harambat, Jerome; Trautmann, Agnes; Peco-Antic, Amira; Borzecka, Halina; Moczulska, Anna; Saeed, Bassam; Bogdanovic, Radovan; Kalyoncu, Mukaddes; Simkova, Eva; Erdogan, Ozlem; Vrljicak, Kristina; Teixeira, Ana; Azocar, Marta; Schaefer, Franz.

In: Kidney International, Vol. 85, No. 5, 2014, p. 1169-1178.

Research output: Contribution to journalArticle

Lipska, BS, Ranchin, B, Iatropoulos, P, Gellermann, J, Melk, A, Ozaltin, F, Caridi, G, Seeman, T, Tory, K, Jankauskiene, A, Zurowska, A, Szczepanska, M, Wasilewska, A, Harambat, J, Trautmann, A, Peco-Antic, A, Borzecka, H, Moczulska, A, Saeed, B, Bogdanovic, R, Kalyoncu, M, Simkova, E, Erdogan, O, Vrljicak, K, Teixeira, A, Azocar, M & Schaefer, F 2014, 'Genotype-phenotype associations in WT1 glomerulopathy', Kidney International, vol. 85, no. 5, pp. 1169-1178. https://doi.org/10.1038/ki.2013.519
Lipska BS, Ranchin B, Iatropoulos P, Gellermann J, Melk A, Ozaltin F et al. Genotype-phenotype associations in WT1 glomerulopathy. Kidney International. 2014;85(5):1169-1178. https://doi.org/10.1038/ki.2013.519
Lipska, Beata S. ; Ranchin, Bruno ; Iatropoulos, Paraskevas ; Gellermann, Jutta ; Melk, Anette ; Ozaltin, Fatih ; Caridi, Gianluca ; Seeman, Tomas ; Tory, K. ; Jankauskiene, Augustina ; Zurowska, Aleksandra ; Szczepanska, Maria ; Wasilewska, Anna ; Harambat, Jerome ; Trautmann, Agnes ; Peco-Antic, Amira ; Borzecka, Halina ; Moczulska, Anna ; Saeed, Bassam ; Bogdanovic, Radovan ; Kalyoncu, Mukaddes ; Simkova, Eva ; Erdogan, Ozlem ; Vrljicak, Kristina ; Teixeira, Ana ; Azocar, Marta ; Schaefer, Franz. / Genotype-phenotype associations in WT1 glomerulopathy. In: Kidney International. 2014 ; Vol. 85, No. 5. pp. 1169-1178.
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AU - Lipska, Beata S.

AU - Ranchin, Bruno

AU - Iatropoulos, Paraskevas

AU - Gellermann, Jutta

AU - Melk, Anette

AU - Ozaltin, Fatih

AU - Caridi, Gianluca

AU - Seeman, Tomas

AU - Tory, K.

AU - Jankauskiene, Augustina

AU - Zurowska, Aleksandra

AU - Szczepanska, Maria

AU - Wasilewska, Anna

AU - Harambat, Jerome

AU - Trautmann, Agnes

AU - Peco-Antic, Amira

AU - Borzecka, Halina

AU - Moczulska, Anna

AU - Saeed, Bassam

AU - Bogdanovic, Radovan

AU - Kalyoncu, Mukaddes

AU - Simkova, Eva

AU - Erdogan, Ozlem

AU - Vrljicak, Kristina

AU - Teixeira, Ana

AU - Azocar, Marta

AU - Schaefer, Franz

PY - 2014

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N2 - WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype-phenotype correlations of 61 patients with WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype-phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.

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