Clinical Characterization of a National Cohort of Patients With Germline WT1 Variants Including Late-Onset Phenotypes

Abstract

Introduction: WT1 disorder is a recently introduced term for phenotypes associated with germline Wilms Tumor 1 (WT1) variants, including glomerulopathy, urogenital anomalies, and Wilms tumor. Previous studies showed a bias toward missense variants in the DNA-binding/Zinc-finger domain of WT1 (exon 8 and 9) and patients with early-onset glomerulopathy. Thorough genotype-phenotype correlations including follow-up data on late-onset glomerulopathy risk are lacking. To characterize the genotypic and phenotypic spectrum of WT1 disorder, we describe a national cohort of individuals with WT1 variants.

Methods: We requested clinical and genetic data of all patients with germline WT1 variants at all Dutch genetic laboratories.

Results: We identified 43 patients with pathogenic WT1 variants (truncating, n = 19; missense, n = 13; splice-site, n = 7; and deletions, n = 4). Wilms tumor was the only clinical manifestation in 10 patients, of whom 9 were female. Wilms tumor occurred in 18 of 19 patients with truncating variants, in 4 of 4 patients with deletions, and was rarer in patients with missense or splice-site variants. All patients with missense and 6 of 7 with splice-site variants developed chronic kidney disease (CKD) versus 5 of 19 patients with truncating variants (3 in adulthood, with kidney failure at the age of 24, 26, and 41 years) and 1 of 4 with a deletion. Urogenital malformations occurred predominantly in 46,XY individuals.

Conclusion: Among patients with WT1 variants, a genotype-phenotype correlation was observed for Wilms tumor risk and age of CKD onset. Although childhood-onset CKD was more common in patients with missense variants in the DNA-binding/Zinc-finger domain, other patients may develop CKD and kidney failure later in life. Therefore, life-long surveillance of kidney function is recommended. Being alert about WT1 variants is especially important for girls with Wilms tumor who often miss additional phenotypes.

Keywords: Denys-Drash; WT1; Wilms tumor.

Graphical abstract

Figure 1

Representation of variants according to location in the WT1 gene matched to phenotype (WT1 transcript NM_024426). (a) cDNA position of the variant and patient age at moment of inclusion. m, months; y, years; ∗patient was previously published in Segers, H. et al 2012. (b) Phenotype of the patients represented by their specific variant in (a), the deletions are not represented. CKD, chronic kidney disease. (c) Illustrates the location of the variants in the gene as per domain and exon number.

Figure 2

Proportion of patients with a given phenotype, according to genetic variant type. CKD, chronic kidney disease.

Figure 3

Survival analysis of kidney function.