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Abstract: TH-PO655

Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Whole Genome Sequencing

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Lanktree, Matthew B., University Health Network, Toronto General Hospital, Toronto, Ontario, Canada
  • Haghighi, Amirreza, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada
  • Guiard, Elsa, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada
  • Iliuta, Ioan-Andrei, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada
  • Song, Xuewen, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada
  • Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
  • Paterson, Andrew, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Pei, York P., University Health Network, Toronto General Hospital, Toronto, Ontario, Canada
Background

Estimating the prevalence of Autosomal Dominant Polycystic Kidney Disease (ADPKD) is challenging due to age-dependent penetrance and incomplete clinical ascertainment. ADPKD has an estimated lifetime risk of ~1 in 1000, while recent epidemiologic studies report a point prevalence of 3-5/10,000. Severe Autosomal Dominant Polycystic Liver Disease (ADPLD) is rare (<1 in 100,000), but milder forms may be clinically unrecognized. Quantity of functional polycystin-1 is a common genetic link between ADPKD and ADPLD. Using two large population sequencing databases, we estimated the lifetime prevalence of cystic kidney and liver diseases using stringent criteria for defining pathogenic variants.

Methods

Rare variants identified in genes involved in ADPKD (PKD1, PKD2), ADPLD (SEC63, PRKCSH, GANAB, ALG8, SEC61B, LRP5) and potential cystic disease modifiers (PKHD1, DZIP1L, UMOD, REN, MUC1, TSC1, TSC2, HNF1B, VHL, COL4A1, COL4A3, COL4A4, COL4A5) were obtained from whole genome and exome sequencing from gnomAD (ngenomes=15,496, nexomes=123,136) and BRAVO (ngenomes=62,784). Variants were evaluated for quality and annotation, compared with the Mayo PKD mutation database, and evaluated by bioinformatic prediction.

Results

High confidence pathogenic mutations in whole genome sequencing provides a lower bound lifetime ADPKD prevalence of 9.3/10,000 (95% confidence interval, 7.2 to 11.5). Estimates from whole genome and exome data were not statistically different. No significant differences in prevalence were observed between ethnicities. Protein truncating mutations in ADPLD genes and potential cyst modifier genes were found in 20.2/10,000 (95% confidence interval, 18.2 to 22.1) and 124.8/10,000 (95% CI, 119.4 to 129.1), respectively.

Conclusion

Population whole genome and exome sequencing supports a lower bound lifetime prevalence of ADPKD of about 1 in 1000. Truncation mutations in genes causative of ADPLD are surprisingly common, found in about 1 in 500. Individually rare variants in other cystic genes are cumulatively common and have the potential to modify the phenotype of ADPKD.

Funding

  • Private Foundation Support