title: Genotype-phenotype associations in WT1 glomerulopathy.
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.
authors.affiliation: 1] Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland [2] Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: Beata S
authors.initials: BS
authors.lastname: Lipska
authors.affiliation: Service de Néphrologie Pédiatrique, Centre de Référence des Maladies Rénales Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon and Université de Lyon, Bron, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ranchin
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Centre for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Paraskevas
authors.initials: P
authors.lastname: Iatropoulos
authors.affiliation: Klinik für Pädiatrie/Nephrologie, Charité Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Gellermann
authors.affiliation: Pediatric Kidney, Liver and Metabolic Disease, MHH Children's Hospital, Hannover, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Melk
authors.affiliation: 1] Departments of Pediatric Nephrology and Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey [2] Nephrogenetics Laboratory, Hacettepe University Faculty of Medicine, Ankara, Turkey.
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozaltin
authors.affiliation: Laboratorio di Fisiopatologia dell'Uremia e UOC di Nefrologia Dialisi e Trapianto, Istituto G Gaslini, Genova, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Caridi
authors.affiliation: 1] 1st Department of Pediatrics, University Hospital Motol, Prague, Czech Republic [2] 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Seeman
authors.affiliation: 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Kalman
authors.initials: K
authors.lastname: Tory
authors.affiliation: Vilnius University, Vilnius, Lithuania.
authors.forename: Augustina
authors.initials: A
authors.lastname: Jankauskiene
authors.affiliation: Department Paediatrics, Nephrology and Hypertension, Medical University Gdansk, Gdansk, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Zurowska
authors.affiliation: Dialysis Division for Children, Department and Clinics of Pediatrics, Medical University of Silesia in Katowice, Zabrze, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Szczepanska
authors.affiliation: Department of Pediatric Nephrology, University of Bialystok, Bialystok, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wasilewska
authors.affiliation: Service de Pédiatrie, Centre de Référence Maladies Rénales Rares du Sud Ouest, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Harambat
authors.affiliation: Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Trautmann
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital, Belgrade, Serbia.
authors.forename: Amira
authors.initials: A
authors.lastname: Peco-Antic
authors.affiliation: Medical University Lublin, Pediatric Nephrology, Lublin, Poland.
authors.forename: Halina
authors.initials: H
authors.lastname: Borzecka
authors.affiliation: Department of Pediatric Nephrology, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Moczulska
authors.affiliation: Department of Pediatric Nephrology, Kidney Hospital, Damascus, Syria.
authors.forename: Bassam
authors.initials: B
authors.lastname: Saeed
authors.affiliation: Department of Nephrology, Institute of Mother and Child Healthcare of Serbia, Belgrade, Serbia.
authors.forename: Radovan
authors.initials: R
authors.lastname: Bogdanovic
authors.affiliation: Karadeniz Technical University, Faculty of Medicine, Pediatric Nephrology Department, Trabzon, Turkey.
authors.forename: Mukaddes
authors.initials: M
authors.lastname: Kalyoncu
authors.affiliation: Paediatric Department, Dubai Hospital, Dubai, UAE.
authors.forename: Eva
authors.initials: E
authors.lastname: Simkova
authors.affiliation: Department of Pediatric Nephrology, Dr. Sami Ulus Maternity and Children's Hospital, Ankara, Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Erdogan
authors.affiliation: Division of Nephrology, Department of Pediatrics, Zagreb University Hospital Centre, University of Zagreb, Zagreb, Croatia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Vrljicak
authors.affiliation: Pediatric Nephrology, University Children's Hospital, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Teixeira
authors.affiliation: Unidad de Nefrología Infantil Hospital Luis Calvo Mackenna, Facultad de Medicina Universidad de Chile, Santiago de Chile, Chile.
authors.forename: Marta
authors.initials: M
authors.lastname: Azocar
authors.affiliation: Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
mesh_terms: D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D005923:Glomerulosclerosis, Focal Segmental / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D009154:Mutation; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics / Q000628:therapy; D010641:Phenotype; D015995:Prevalence; D011379:Prognosis; D012042:Registries; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D012307:Risk Factors; D013997:Time Factors; D025721:WT1 Proteins / Q000235:genetics*
chemical_list: D025721:WT1 Proteins; C583751:WT1 protein, human