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 language | English |
|---|---|
| Pages (from-to) | 1169-1178 |
| Number of pages | 10 |
| Journal | Kidney International |
| Volume | 85 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2014 |
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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
Genotype-phenotype associations in WT1 glomerulopathy. / Lipska, Beata S.; Ranchin, Bruno; Iatropoulos, Paraskevas; Gellermann, Jutta; Melk, Anette; Ozaltin, Fatih; Caridi, Gianluca; Seeman, Tomas; Tory, Kalman; 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 journal › Article
}
TY - JOUR
T1 - Genotype-phenotype associations in WT1 glomerulopathy
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, Kalman
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
Y1 - 2014
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.
AB - 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.
KW - Denys-Drash syndrome
KW - Diffuse mesangial sclerosis
KW - Focal segmental glomerulosclerosis
KW - Frasier syndrome
KW - Steroid-resistant nephrotic syndrome
KW - WT1
UR - http://www.scopus.com/inward/record.url?scp=84899907617&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899907617&partnerID=8YFLogxK
U2 - 10.1038/ki.2013.519
DO - 10.1038/ki.2013.519
M3 - Article
VL - 85
SP - 1169
EP - 1178
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 5
ER -