Correlation between PKD1 Mutation Type and Height-Adjusted Total Kidney Volume in Chinese Patients with ADPKD: Genotype-Phenotype Analysis

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disease but with allelic and genetic heterogeneity. This study aims to explore the association between PKD1 mutation types and height-adjusted total kidney volume (htTKV) in Chinese ADPKD patients. Methods: We evaluated genotype-phenotype correlations in 379 subjects with affected ADPKD between August 25, 2017 and April 2, 2024. Patients with complex genotypes (mosaic, digenic, or diallelic) were excluded. We performed regression analysis to examine the effects of age, sex, and mutation type on htTKV natural log scale. Results: 90.5% of the patients got molecularly diagnosed with PKD1 (82.3%, n=312) and PKD2 (7.9%, n=30) in the current study. PKD1 truncating mutations accounts for 67.3% of the patients (Figure 1). Men had more severe disease than women with lower eGFR and larger htTKV (Figure 2, A and B). Patients with nonsense and frameshift mutations showed faster eGFR decline compared to missense mutations (Figure 2C). Patients with PKD1 truncating mutations generally have larger htTKV than non-truncating mutations (P<0.005) (Figure 2D). Allelic effect on htTKV was more significant in splicing, frameshift and nonsense mutation classes (Figure 2E). Conclusion: In Chinese ADPKD patients, we confirmed that kidney cyst severity differs by mutation types in PKD1. Patients with PKD1 truncating mutations have higher TKV and lower eGFR, particularly frameshift and nonsense mutations. Assessment of mutation types may predict renal prognosis and aid in caring for high-risk ADPKD patients.Figure 1. Categories of mutation type in PKD1 population.Figure 2. Sex and allelic effects on ADPKD phenotype in PKD1 population.