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.

] 1st Department of Pediatrics University Hospital Motol Prague Czech Republic [2] 2nd Faculty of Medicine Charles University Prague Czech Republic

] 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

] Departments of Pediatric Nephrology and Rheumatology Hacettepe University Faculty of Medicine Ankara Turkey [2] Nephrogenetics Laboratory Hacettepe University Faculty of Medicine Ankara Turkey

1st Department of Pediatrics Semmelweis University Budapest Hungary

Department of Nephrology Institute of Mother and Child Healthcare of Serbia Belgrade Serbia

Department of Pediatric Nephrology Dr Sami Ulus Maternity and Children's Hospital Ankara Turkey

Department of Pediatric Nephrology Jagiellonian University Medical College Krakow Poland

Department of Pediatric Nephrology Kidney Hospital Damascus Syria

Department of Pediatric Nephrology University of Bialystok Bialystok Poland

Department Paediatrics Nephrology and Hypertension Medical University Gdansk Gdansk Poland

Dialysis Division for Children Department and Clinics of Pediatrics Medical University of Silesia in Katowice Zabrze Poland

Division of Nephrology Department of Pediatrics Zagreb University Hospital Centre University of Zagreb Zagreb Croatia

Division of Pediatric Nephrology Center for Pediatrics and Adolescent Medicine University of Heidelberg Heidelberg Germany

Division of Pediatric Nephrology University Children's Hospital Belgrade Serbia

IRCCS Istituto di Ricerche Farmacologiche Mario Negri Clinical Research Centre for Rare Diseases Aldo e Cele Daccò Ranica Bergamo Italy

Karadeniz Technical University Faculty of Medicine Pediatric Nephrology Department Trabzon Turkey

Klinik für Pädiatrie Nephrologie Charité Campus Virchow Klinikum Berlin Germany

Laboratorio di Fisiopatologia dell'Uremia e UOC di Nefrologia Dialisi e Trapianto Istituto G Gaslini Genova Italy

Medical University Lublin Pediatric Nephrology Lublin Poland

Paediatric Department Dubai Hospital Dubai UAE

Pediatric Kidney Liver and Metabolic Disease MHH Children's Hospital Hannover Germany

Pediatric Nephrology University Children's Hospital Porto Portugal

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

Service de Pédiatrie Centre de Référence Maladies Rénales Rares du Sud Ouest Centre Hospitalier Universitaire de Bordeaux Bordeaux France

Unidad de Nefrología Infantil Hospital Luis Calvo Mackenna Facultad de Medicina Universidad de Chile Santiago de Chile Chile

Vilnius University Vilnius Lithuania

Citace poskytuje Crossref.org

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