Kidney Week

Abstract: FR-PO0151

WT1 Variants and Their Association with Podocytopathy Across the Lifespan

Session Information

• Hereditary Glomerular and Tubulointerstitial Kidney Diseases
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Mann, Nina, Nationwide Children's Hospital, Columbus, Ohio, United States

Nina Mann, MD

• Martinelli, Elena, Columbia University, New York, New York, United States

Elena Martinelli, MD

• Lai Yee, Jennifer, University of Michigan, Ann Arbor, Michigan, United States

Jennifer Lai Yee, MD, PhD, MPH

• Ke, Juntao, Columbia University, New York, New York, United States

Juntao Ke, PhD

• Beenken, Andrew Samuel, Columbia University, New York, New York, United States

Andrew Samuel Beenken, MD, PhD

• Bilgin, Feride Melisa, Nationwide Children's Hospital, Columbus, Ohio, United States

Feride Melisa Bilgin, MS, MSc

• Zion, Elena, Boston Children's Hospital, Boston, Massachusetts, United States

Elena Zion, MD

• Marchuk, Daniel, Boston Children's Hospital, Boston, Massachusetts, United States

Daniel Marchuk, MD

• Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States

Matthias Kretzler, MD

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk, MD

• Gharavi, Ali G., Columbia University, New York, New York, United States

Ali G. Gharavi, MD

• Caliskan, Yasar, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Yasar Caliskan, MD

• Zanoni, Francesca, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Francesca Zanoni, MD

• Simões e Silva, Ana Cristina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil

Ana Cristina Simões e Silva, MD, PhD

• Pisani, Isabella, Universita degli Studi di Parma Dipartimento di Medicina e Chirurgia, Parma, Emilia-Romagna, Italy

Isabella Pisani, MD

• Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy

Loreto Gesualdo, MD

• Reiterová, Jana, Univerzita Karlova, Prague, Czechia

Jana Reiterová

• Ghiggeri, Gian Marco, Istituto Giannina Gaslini IRCCS, Genoa, Italy

Gian Marco Ghiggeri, MD

• Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States

Matt G. Sampson, MD

• Saleem, Moin A., University of Bristol, Bristol, England, United Kingdom

Moin A. Saleem, MD, MBBS, MBChB, PhD

• Gbadegesin, Rasheed A., Duke University Medical Center, Durham, North Carolina, United States

Rasheed A. Gbadegesin, MD, MBBS, FASN

• Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Martin Pollak, MD

• Kitzman, Jacob O., University of Michigan, Ann Arbor, Michigan, United States

Jacob O. Kitzman, PhD

• Sanna-Cherchi, Simone, Columbia University, New York, New York, United States

Simone Sanna-Cherchi, MD

• Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt, MD

Background

Wilms tumor 1, or WT1, is a transcription factor that is essential for kidney development and function of the mature podocyte. Human variants in WT1 cause WT1-associated podocytopathy (WT1-AP), which has historically been considered a disease of childhood. Here we describe the natural history of WT1-AP in a large cohort of patients across the lifespan and expand upon the recognized clinical and genetic spectrum of disease.

Methods

Exome sequencing was performed in an international cohort of 5,389 individuals with idiopathic nephrotic syndrome and/or fixed proteinuria. We analyzed genomic data for rare, likely deleterious variants in WT1 and collected clinical data from contributing centers nationally and internationally. Structural and functional analyses were performed to assess the pathogenicity of novel WT1 variants.

Results

We identified 20 unique WT1 variants in 43 affected individuals from 42 unrelated families. There was a wide range in the age of clinical recognition (10 days to 47 years) and age at kidney failure (1 month to 67 years). Individuals with variants affecting the zinc-chelating or DNA-base recognizing residues within one of WT1’s four zinc finger domains presented at an earlier age and had more rapid progression to kidney failure. In contrast, individuals with variants that affected other residues within the zinc finger domains more frequently presented in adulthood with fixed proteinuria and had a more indolent disease course. Functional studies demonstrated that these hypomorphic variants result in partial, but not full, loss of WT1 transcriptional activity.

Conclusion

Through exome sequencing of a large, age-diverse cohort with proteinuric kidney disease, we show that WT1-AP can manifest in adulthood with isolated proteinuria and can exhibit a more indolent course than previously recognized. Taken together, our findings redefine WT1-AP as a continuous spectrum of disease across age and severity rather than a set of discrete pediatric syndromes and highlight the importance of variant-level interpretation in precision nephrology.

Funding

• NIDDK Support