Genotype-Phenotype Characterization of PKD1 Missense Variants in ADPKD: Insights from Structural Imaging Biomarkers

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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

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