Genotype-phenotype associations in WT1 glomerulopathy.

Area of Science:

• Nephrology
• Genetics
• Pediatric Nephrology

Background:

• WT1 mutations are associated with diverse renal and extrarenal conditions.
• Steroid-resistant nephrotic syndrome (SRNS) presents a diagnostic challenge, with WT1 mutations being a key genetic factor in a subset of patients.

Purpose of the Study:

• To evaluate disease prevalence, phenotype spectrum, and genotype-phenotype correlations in WT1-related SRNS compared to WT1-negative SRNS.
• To establish the significance of WT1 gene screening in pediatric SRNS.

Main Methods:

• Comparative analysis of 61 patients with WT1-related SRNS and 700 WT1-negative SRNS patients.
• Detailed evaluation of clinical presentation, renal biopsy findings, disease progression, and genetic mutations.

Main Results:

• WT1 patients showed higher rates of chronic kidney disease, hypertension, and faster progression. Diffuse mesangial sclerosis was specific to WT1 disease (34%).
• Extrarenal manifestations including sex reversal (52%), Wilms tumor (38%), and gonadoblastoma (5%) were predominantly observed in WT1 patients.
• Specific mutation types correlated with distinct phenotypes: missense mutations with diffuse mesangial sclerosis and rapid progression, truncating mutations with high Wilms tumor risk, and intronic (KTS) mutations with isolated SRNS and slower progression.

Conclusions:

• WT1-associated nephropathy exhibits wide expressivity, strong genotype-phenotype associations, and significant extrarenal complications.
• Genetic screening for WT1 mutations is recommended for all children diagnosed with steroid-resistant nephrotic syndrome to guide management and predict outcomes.