Kidney Week

Abstract: FR-PO0095

PKD2 Nontruncating Pathogenic Variant Location Associates with Mayo Imaging Classification (MIC) and Disease Progression in ADPKD

Session Information

• ADPKD and Cystic Kidney Disease - 2
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Jochum, Elena, The University of Chicago, Chicago, Illinois, United States

Elena Jochum

• Marquez Nogueras, Karla Marie, Loyola University Chicago Stritch School of Medicine, Chicago, Illinois, United States

Karla Marie Marquez Nogueras, PhD

• Chen, Peili, The University of Chicago Department of Medicine, Chicago, Illinois, United States

Peili Chen, MD, PhD

• Wessely, Oliver, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States

Oliver Wessely, PhD

• Kuo, Ivana Y., Loyola University Chicago Stritch School of Medicine, Chicago, Illinois, United States

Ivana Y. Kuo, PhD

• Chapman, Arlene B., The University of Chicago Department of Medicine, Chicago, Illinois, United States

Arlene B. Chapman, MD

Background

ADPKD is the fourth most common cause of end stage kidney disease and is caused primarily by mutations in PKD1 or PKD2. The location of non-truncating pathogenic variants in PKD1 has been shown to impact disease severity as defined by MIC, height-adjusted total kidney volume (htTKV), and estimated glomerular filtration rate (eGFR). In PKD2, over 80% of pathogenic missense variants are located in the TOP domain, yet it is unclear if location impacts disease severity. Therefore, we evaluated the location of non-truncating pathogenic variants in PKD2 in association with MIC, htTKV, and eGFR.

Methods

A comprehensive dataset of 207 unrelated PKD2 patients was assembled from the HALT A/B clinical trials, CRISP study, the University of Chicago ADPKD Center of Excellence Cohort, and the Mayo ADPKD Variant Database. Molecular domains were assigned to patients based on variant location, and the distribution of pathogenic variants in the polycystin-2 protein was mapped in association with MIC, htTKV, and eGFR progression.

Results

PKD2 truncating variants were distributed evenly throughout polycystin-2, while non-truncating variants clustered in functional domains, particularly the transmembrane (aa 204-687) and TOP domains (aa 242-468) (Fig 1). Variants in the TOP domain showed 46.2% high risk MIC (1C-E) vs. 16.7% for non-TOP variants. Patients with TOP domain variants demonstrated greater htTKV growth rates (7.88+/-2.08% vs. 3.04+/-1.62%, P<0.003) and a trend of faster eGFR decline in patients 25 years or older (-2.02+/-1.31 mL/min/yr vs. -1.03+/-1.63 mL/min/yr, P<0.07).

Conclusion

Patients with non-truncating PKD2 pathogenic variants are overrepresented in functional domains, with those in the TOP domain associating with high risk MIC, increased rate of htTKV growth and decline in eGFR. These findings indicate that location of missense variants may be a target for therapeutic intervention and a prognostic marker for PKD2 patients.

Figure 1. Distribution of non-truncating PKD2 variants in the polycystin-2 protein with associated MIC.