Genotype-phenotype associations in WT1 glomerulopathy
Language English Country United States Media print-electronic
Document type Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
PubMed
24402088
DOI
10.1038/ki.2013.519
PII: S0085-2538(15)56331-X
Knihovny.cz E-resources
- MeSH
- Time Factors MeSH
- Renal Insufficiency, Chronic diagnosis epidemiology genetics therapy MeSH
- Child MeSH
- Phenotype MeSH
- Glomerulosclerosis, Focal Segmental diagnosis epidemiology genetics therapy MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Association Studies MeSH
- Genetic Testing methods MeSH
- Incidence MeSH
- Infant MeSH
- Humans MeSH
- Mutation * MeSH
- DNA Mutational Analysis MeSH
- Nephrotic Syndrome congenital diagnosis epidemiology genetics therapy MeSH
- Child, Preschool MeSH
- Prevalence MeSH
- Prognosis MeSH
- Disease Progression MeSH
- WT1 Proteins genetics MeSH
- Registries MeSH
- Risk Factors MeSH
- Age of Onset MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- WT1 Proteins MeSH
- WT1 protein, human MeSH Browser
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 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
Division of Pediatric Nephrology University Children's Hospital Belgrade Serbia
Karadeniz Technical University Faculty of Medicine Pediatric Nephrology Department Trabzon Turkey
Klinik für Pädiatrie Nephrologie Charité Campus Virchow Klinikum Berlin Germany
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
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