Genotype–phenotype associations in WT1 glomerulopathy

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.

Clinical and Molecular Characterization of Patients with Heterozygous Mutations in Wilms Tumor Suppressor Gene 1

“…Our study confirms the more rapid progression toward ESRD for patients with exon mutations compared with those with KTS splice site mutations, as described by Chernin et al (19). We documented a differential effect of type of exon mutations on onset of proteinuria and renal failure, confirming the findings of Lipska et al (16). Patients with missense mutations in exon 8/9 tend to have an earlier onset of nephropathy than patients with truncating or KTS splice site mutations.…”

“…Compared with the data by Lipska et al (16), the frequency of exon mutations is higher in our cohort (66% versus 83%). We could not confirm a significant effect of missense mutations residing in DNA-binding regions compared with other parts of the WT1 gene.…”

“…We describe a significant phenotypic variability caused by the same single mutation regarding WT development and genitourinary malformations. Lipska et al (16) included nine patients with this mutation but performed only a limited subanalysis.…”

“…Over the past years, many clinical pictures beyond the classic syndromes have been described in patients with heterozygous WT1 mutations, illustrating the phenotypic heterogeneity (14,15). A recent report by the international PodoNet Consortium described genotype/phenotype correlations associated with WT1 mutations in 61 patients with nephrotic syndrome collected worldwide; it did not cover treatment of proteinuria (16).…”

It is time to take timing seriously in clinical genetics

“…Screening studies in a cohort of patients with steroid-resistant nephrotic syndrome suggest an inverse relationship of the rate of genetic diagnosis with age, the prevalence figures of genetic causes ranging from 100% downward to 57%, 36%, and 14% for congenital-onset, infantile-onset, childhoodonset, and adult-onset cases, respectively, suggesting that the clinical utility of genetic testing for a diagnostic purpose depends on the age of the patients. 26,27 Accordingly, the current guidelines on ethical issues involving the definition of personal data, privacy, identifiability, and confidentiality, moreover, controlling biobanking, may possess reconsideration to meet the concept of dynamic changes in the genome during the lifetime. 28 30 It is worth investigating whether the genome's plasticity in the function of time, the fourth dimension of the genetic control of life, may be a possible reason behind the 'missing heritability'.…”