Abstract: SA-PO0568
Genotype-Phenotype Characterization of PKD1 Missense Variants in ADPKD: Insights from Structural Imaging Biomarkers
Session Information
- Cystic Kidney Diseases: Clinical Research
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Bou Antoun, Marie Therese, Mayo Clinic in Florida, Jacksonville, Florida, United States
- Borghol, Abdul Hamid, Mayo Clinic in Florida, Jacksonville, Florida, United States
- Munairdjy Debeh, Fadi George, Mayo Clinic in Florida, Jacksonville, Florida, United States
- Ghanem, Ahmad, Mayo Clinic in Florida, Jacksonville, Florida, United States
- Gregory, Adriana, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Yang, Hana, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Schauer, Rachel S., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Hanna, Christian, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Kline, Timothy L., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Chebib, Fouad T., Mayo Clinic in Florida, Jacksonville, Florida, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD), primarily caused by PKD1 and PKD2 pathogenic variants, leads to kidney failure by mid-adulthood. While PKD1 truncating variants (PKD1T) are associated with more severe disease than PKD2 variants, the clinical impact of PKD1 missense variants is less well established. This study aimed to define the genotype–phenotype relationships of PKD1 missense variants using structural imaging biomarkers.
Methods
We retrospectively analyzed 584 genetically confirmed ADPKD patients enrolled in the Mayo Clinic PKD registry: PKD1T (51.7%), PKD1 missense (26.2%), and PKD2 (22.1%). Kidney volume and cyst burden were quantified using cyst segmentation. Imaging biomarkers were compared across genotypes.
Results
PKD1 missense and PKD2 patients showed comparable renal parenchymal volume (htRPV), cyst-parenchymal surface area (CPSA), and total cyst volume (htTCV), significantly lower than those in PKD1T. Cyst counts were highest in PKD1T, followed by PKD1 missense, then PKD2 (p<0.01, Table 1). MIC 1C-1E was most frequent in PKD1T (79%), but also present in 52% of PKD1 missense and 54% of PKD2 (p<0.01). Annual growth rates of total kidney volume (TKV), TCV, RPV, CPSA, and total cyst number (TCN) did not differ significantly by genotype. However, among PKD1 missense, variants located in the 5′ region were associated with faster growth in TKV (+2.7%, p<0.01), TCV (+9.4%, p<0.01), cyst surface area (CSA; +6.8%, p<0.01), and CPSA (+6.5%, p<0.01) compared to 3′ variants.
Conclusion
Although PKD1 missense variants confer an intermediate phenotype between PKD1T and PKD2, these patients still have high cyst burden including elevated TKV and TCN. Half meet MIC criteria for risk of rapid progression, underscoring the clinical relevance of PKD1 missense variants.
Table 1: Baseline Characteristics
| PKD1T (N=302) | PKD1 Missense (N=153) | PKD2 (N=129) | p-value | |
| Age at imaging (yrs), mean (±SD) | 39.2 (11.8) | 45.5 (13.8) | 49.0 (14.4) | <0.001 |
| Females, N(%) | 200 (66.2%) | 96 (62.8%) | 77 (59.7%) | 0.21 |
| Height-adjusted total kidney volume (htTKV) (mL/m), median (Q1 , Q3) | 770.2 (491.4 , 1248.1) | 579.1 (352.5 , 1149.7) | 648.0 (342.2 , 1387.6) | <0.001 |
| MIC 1C, D, or E, N(%) | 238 (79%) | 80 (52%) | 68 (54%) | <0.001 |
| Height-adjusted total cyst volume (htTCV) (mL), median (Q1 ,Q3) | 326.6 (149.6 , 618.4) | 178.3 (88.3 , 501.5) | 278.6 (82.9 , 776.7) | 0.013 |
| Cyst-parenchymal surface area (CPSA) (cm2), median (Q1 , Q3) | 1195.4 (686.3 , 2138.2) | 879.6 (435.6 , 1667.8) | 759.0 (309.4 , 1632.7) | <0.001 |
| Total cyst number (TCN), median (Q1 , Q3) | 382.0 (230.5 , 601.0) | 316.0 (165.5 , 513.0) | 222.0 (119.0 , 425.3) | <0.001 |