Genetic and Clinical Profiles of ADPKD in Two Population-Based Cohorts

Background: Most ADPKD cases are caused by PKD1 or PKD2. Additional genes have been recently linked to atypical cases, but some ADPKD cases remain genetically unresolved. We studied two population-based cohorts with whole-exome sequencing (WES) and clinical/imaging data to characterize the genetic spectrum and phenotypic variability of ADPKD. Methods: We studied 52,786 Mayo Clinic Biobank (MCBB) and 82,445 Tapestry participants. We screened ADPKD candidates via ICD-9/10 kidney cyst codes and screened for truncating (T) and nontruncating (NT) variants in PKD1, PKD2, and only T in the minor ADPKD genes. Patient charts and imaging were reviewed. Results: An ADPKD-spectrum was confirmed in 159 (0.3%) MCBB and 212 (0.26%) Tapestry participants. In MCBB, PKD1-T, PKD1-NT, PKD2, and minor gene variants accounted for 31%, 15%, 14.5%, and 12% of cases, respectively. In Tapestry, these genes accounted for 39%, 24.5%, 13%, and 7%. The remainder (27.6% in MCBB; 17.5% in Tapestry) had no identified causative variants. Genotype correlated with disease severity: PKD1-T variant carriers had larger htTKV than other gene carriers (Figure 1). After adjusting for age (centering at the overall mean of 60.6 years), the estimated mean eGFR was 34 mL/min/1.73m2 in MCBB and 54 mL/min/1.73m2 in Tapestry (p<0.001) suggesting Tapestry has more mild patients. Population-wide screening for T variants in minor ADPKD genes showed reduced penetrance; for each gene, carriers developed >10 cysts in <50% of cases with enhanced CT or MR imaging (Table 1). Conclusion: Using population-based genetic and phenotypic data, we captured a full ADPKD spectrum and gene-dependent variability. Our findings indicate high penetrance for PKD1/PKD2 but variable penetrance of the minor genes. These data highlight the value of population approaches and the potential to identify additional ADPKD genetic causes and modifiers. Funding: NIDDK Support