Population Frequency of Undiagnosed Pathogenic Variants in PKD Type 1 and Type 2

Background: The estimated population frequency of AD polycystic kidney disease in recent epidemiologic studies has varied from one in 1000 to one in 2000 but when based on a genetic analysis is closer to one in 1000 (PMID:30135240). This study has reexamined the commonest genes affected, PKD1 and PKD2, for pathogenic variants including assessing missense changes with highly stringent criteria, with Alamut and REVEL, in order to more accurately determine the ADPKD population frequency. Methods: PKD1 and PKD2 variants were downloaded from gnomAD v2.1 and annotated in ANNOVAR. Structural and null variants were considered pathogenic and missense variants assessed for pathogenicity based on rarity, positivity in three computational tools and whether they affected a residue conserved in vertebrates. The occurrence of these variants in people of different ancestries was also examined. Our approach for assessing missense variants was compared with positivity in Alamut (scores >5 or >6), and REVEL (>0.932), and the accuracy of these approaches evaluated using 20 benign and 20 pathogenic variants reported in LOVD. Results: One in 1500 of the population have a null PKD1 variant and one in 2500 have a null variant in PKD2. Thus the population frequency of null variants is greater than one in 1000 (8/7500) and 60% of variants affect PKD1. Null variants are most frequently found in people of African/African American, East Asian and South Asian ancestries. Our strategy for assessment of missense changes in PKD1 had a sensitivity of 65% and a specificity of 95%, and missense changes in PKD2 had a sensitivity of 40% and specificity of 100%. However the population frequencies of missense variants were more variable with different approaches. Conclusion: These results suggest that PKD1 and PKD2 pathogenic null and missense variants occur more often in the population than the previously-estimated one in 1000. Missense changes in PKD1 and PKD2 remain difficult to evaluate accurately for pathogenicity. Population frequencies of predicted pathogenic structural, null and missense variants and strategy evaluation - PKD1 Sensitivity Specificity PKD2 Sensitivity Specificity Structural and null variants Total null and structural variants 70 or one in 1500 44 or one in 2500 Comparison of evaluation of missense variants Our assessment 569 or one in 178 65% 95% 81 or one in 1357 40% 100% Alamut > or equal to 5 One in 183 55% 100% One in 1221 55% 90% Alamut > or equal to 6 One in 1400 20% 75% One in 2389 20% 100% REVEL > 0.932 One in 52,534 0% 100% One in 18,318 25% 100%