Abstract: TH-PO0825
Adult-Onset Proteinuric CKD Due to a Novel WT1 Variant: Expanding the Phenotypic Spectrum of WT1-Associated Nephropathy
Session Information
- Glomerular Case Reports: Potpourri
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics
Authors
- Nyabera, Akwe, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, United States
- Donoso-Naranjo, Paola G, Hospital Universitario Virgen del Rocio, Seville, AL, Spain
- Bomback, Andrew S., Columbia University Vagelos College of Physicians and Surgeons, New York, New York, United States
Introduction
WT1-related disorders are associated with pediatric-onset steroid-resistant nephrotic syndrome (SRNS), disorders of sex development (DSD), and Wilms tumor. However, a less common variant of WT1-related SRNS arises from pathogenic variants that disrupt gene splicing, often leading to adult-onset proteinuria, nephrotic syndrome, and potential gonadal dysgenesis. Genetic diagnosis in such cases is crucial, as it influences management, and may obviate the need for invasive procedures or immunosuppression.
Case Description
A 42-year-old male with a history of hypogonadism was referred for evaluation of persistent proteinuria and chronic kidney disease. History was remarkable for foamy urine. Physical exam revealed a BMI of 30.5 kg/m2. Laboratory studies showed serum creatinine 1.40 mg/dL, normal electrolytes, and urine ACR of 1.1 g/g. Renal ultrasound showed preserved kidney size and echogenicity (right 9.0 cm, left 10.0 cm), with a 5 mm non-obstructive lower pole calculus on the left. Genetic testing identified a heterozygous WT1 frameshift variant: c.441_520del (p.Gln147Hisfs30)*, classified as likely pathogenic. A renal biopsy was deferred based on genetic results. He continued on losartan and was initiated on empagliflozin 10 mg daily.
Discussion
This case reports a novel adult-onset presentation of WT1-associated nephropathy, distinct from the typical pediatric phenotype of steroid-resistant nephrotic syndrome (SRNS). The identified variant, c.441_520del (p.Gln147Hisfs*30), represents a previously unreported frameshift mutation leading to loss of WT1 function, located on exon 1. This loss-of-function suggests a different pathogenic mechanism compared to prior identified variants that are associated with a splicing error. Most known WT1 splice variants linked to SRNS cluster near exon 9; however, this mutation lies outside the usual hotspot, suggesting a broader mutational spectrum. Unlike classic early-onset, syndromic presentations with rapid progression to end-stage kidney disease (ESKD), this patient exhibited non-syndromic, slowly progressive chronic kidney disease (CKD) manifesting in adulthood. This case highlights the expanding phenotypic variability of WT1 mutations and underscores the importance of genetic testing in adults with unexplained proteinuric CKD.