Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing

Abstract

Background: Estimating the prevalence of autosomal dominant polycystic kidney disease (ADPKD) is challenging because of age-dependent penetrance and incomplete clinical ascertainment. Early studies estimated the lifetime risk of ADPKD to be about one per 1000 in the general population, whereas recent epidemiologic studies report a point prevalence of three to five cases per 10,000 in the general population.

Methods: To measure the frequency of high-confidence mutations presumed to be causative in ADPKD and autosomal dominant polycystic liver disease (ADPLD) and estimate lifetime ADPKD prevalence, we used two large, population sequencing databases, gnomAD (15,496 whole-genome sequences; 123,136 exome sequences) and BRAVO (62,784 whole-genome sequences). We used stringent criteria for defining rare variants in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5), and potential cystic disease modifiers; evaluated variants for quality and annotation; compared variants with data from an ADPKD mutation database; and used bioinformatic tools to predict pathogenicity.

Results: Identification of high-confidence pathogenic mutations in whole-genome sequencing provided a lower boundary for lifetime ADPKD prevalence of 9.3 cases per 10,000 sequenced. Estimates from whole-genome and exome data were similar. Truncating mutations in ADPLD genes and genes of potential relevance as cyst modifiers were found in 20.2 cases and 103.9 cases per 10,000 sequenced, respectively.

Conclusions: Population whole-genome sequencing suggests a higher than expected prevalence of ADPKD-associated mutations. Loss-of-function mutations in ADPLD genes are also more common than expected, suggesting the possibility of unrecognized cases and incomplete penetrance. Substantial rare variation exists in genes with potential for phenotype modification in ADPKD.

Keywords: ADPKD; disease; genetic renal; human genetics; liver cysts; polycystic kidney disease.

Graphical abstract

Figure 1.

Observed prevalence of ADPKD mutations in population sequencing. (A) Cumulative frequency of high-confidence pathogenic (non-sense, frameshift, and canonical splice site mutations, high-risk in-frame insertions or deletions, or those listed as “definitely” or “highly likely” pathogenic mutations in Mayo PKDB), likely pathogenic (“likely pathogenic” mutations in Mayo PKDB and moderate risk in-frame insertions or deletions), or bioinformatic predicted pathogenic (predicted pathogenic by more than 12 out of 16 bioinformatic algorithms in ANNOVAR) from WGS data. Error bars represent 95% CIs. (B) Proportion of high-confidence pathogenic mutations by mutation class in WGS databases.

Figure 2.

The density of mutations is similar in PKD1 duplicated and unduplicated regions and PKD2. Mutation frequency estimates, corrected for transcript length, from WGS (n=78,280) and WES (n=123,136) data. Error bars represent 95% CIs.

Figure 3.

No difference in ADPKD mutation prevalence was observed between ethnicities. Prevalence of truncating mutations and severe in-frame insertion/deletions in exome sequencing of PKD1 and PKD2 across ethnic groups. Error bars represent 95% CIs.

Figure 4.

ADPLD protein-truncating mutations are more prevalent than expected. Error bars represent 95% CIs.