Genotype/phenotype correlation in nephrotic syndrome caused by WT1 mutations

Abstract

Background and objectives: The risk of developing Wilms tumor (WT) can be present or absent in patients with nephrotic syndrome (NS) caused by WT1 mutations. Here, the genotype/phenotype correlation regarding the outcome and risk for WT in 52 patients from 51 families with NS due to WT1 mutations is described.

Design, setting, participants, & measurements: This study followed 19 patients with mutations in intron 9 splice donor site (KTS mutations), 27 patients with missense mutations, 4 patients with nonsense mutations, 1 patient with a splice site mutation in intron 8, and 1 patient with a deletion.

Results: Twenty-four different WT1 mutations were detected. Sixteen of the 19 patients with KTS mutations were females. These patients had isolated NS if karyotype was 46,XX and Frasier syndrome if karyotype was 46,XY. Patients with KTS mutations presented at a significantly older age and with a slower progression toward chronic kidney disease (CKD) stage 5, compared with missense mutations. Patients with nonsense mutations presented initially with WT. Six patients with missense mutations developed WT after the diagnosis of NS (interval-range from NS onset to WT of 0.1 to 1.4 years).

Conclusions: (1) KTS mutations cause isolated NS with absence of WT in 46,XX females. (2) KTS mutations cause Frasier syndrome with gonadoblastoma risk in 46,XY phenotypic females. (3) KTS mutations cause NS with a slower progression when compared with missense mutations. (4) Missense mutations can occur with and without WT. (5) WT1 analysis is important in young patients with NS for early detection and tumor prophylaxis.

Figure 1.

(Left) NS manifests later in patients with KTS mutations compared with patients with missense mutations in exons 8 or 9 of WT1. Kaplan-Meier survival analysis of interval from birth to onset of NS for 18 patients with splice site mutation in intron 9 (KTS mutations) of WT1 and 27 patients with missense mutations in WT1. The age of NS onset was significantly older in the KTS mutation group compared with patients with missense mutations (t test, P < 0.006). (Right) KTS mutations lead to a slower progression of NS toward CKD stage 5 than missense mutations. Kaplan-Meier survival analysis of interval between onset of NS and CKD stage 5 in 17 patients with splice site mutation in intron 9 (KTS mutations) compared with 26 patients with missense mutations. The vertical latches represent the interval between NS onset and termination of this study for each patient that did not reach CKD stage 5. The interval between onset of NS and CKD stage 5 was significantly longer in the KTS mutation group compared with patients with missense mutations (Log-Rank test, P < 0.006).

Figure 2.

Tumor risk assessment in patients with nephrotic syndrome and WT1 mutations in exons 8 or 9. GB, gonadoblastoma.