title: Clinical and molecular characterization of patients with heterozygous mutations in wilms tumor suppressor gene 1.
abstract: OBJECTIVE
  The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT.
  
  
  METHODS
  Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012.
  
  
  RESULTS
  Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P<0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR, 16.5-16.8]; P<0.001) and splice site mutations (12.3 [IQR, 7.9-18.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations.
  
  
  CONCLUSIONS
  Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material. A.Lehnhardt@uke.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Lehnhardt
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Claartje
authors.initials: C
authors.lastname: Karnatz
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Thurid
authors.initials: T
authors.lastname: Ahlenstiel-Grunow
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Benz
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Benz
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Büscher
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fehr
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Markus
authors.initials: M
authors.lastname: Feldkötter
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Norbert
authors.initials: N
authors.lastname: Graf
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authors.forename: Britta
authors.initials: B
authors.lastname: Höcker
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Therese
authors.initials: T
authors.lastname: Jungraithmayr
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Günter
authors.initials: G
authors.lastname: Klaus
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authors.forename: Birgit
authors.initials: B
authors.lastname: Koehler
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authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
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authors.forename: Birgitta
authors.initials: B
authors.lastname: Kranz
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authors.forename: Carmen R
authors.initials: CR
authors.lastname: Montoya
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authors.forename: Dominik
authors.initials: D
authors.lastname: Müller
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Neuhaus
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Jun
authors.initials: J
authors.lastname: Oh
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Lars
authors.initials: L
authors.lastname: Pape
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Martin
authors.initials: M
authors.lastname: Pohl
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Royer-Pokora
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Uwe
authors.initials: U
authors.lastname: Querfeld
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneppenheim
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Hagen
authors.initials: H
authors.lastname: Staude
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Spartà
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Timmermann
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Frauke
authors.initials: F
authors.lastname: Wilkening
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Simone
authors.initials: S
authors.lastname: Wygoda
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.affiliation: Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Kemper
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001317:Austria; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D016162:Genes, Wilms Tumor; D005858:Germany; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D059785:Karyotype; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000601:surgery; D016030:Kidney Transplantation; D008297:Male; D020125:Mutation, Missense; D009392:Nephrectomy; D010641:Phenotype; D011507:Proteinuria / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D006435:Renal Dialysis; D012189:Retrospective Studies; D013557:Switzerland; D014564:Urogenital Abnormalities / Q000235:genetics*; D009396:Wilms Tumor / Q000175:diagnosis / Q000235:genetics / Q000601:surgery; D055815:Young Adult
keywords: genetic renal disease; nephrotic syndrome; pediatric nephrology
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