Population data improves variant interpretation in autosomal dominant polycystic kidney disease

Amali C. Mallawaarachchi, Timothy J. Furlong, John Shine, Peter C. Harris, Mark J. Cowley

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is a common adult-onset monogenic disorder, with prevalence of 1/1000. Population databases including ExAC have improved pathogenic variant prioritization in many diseases. Due to pseudogene homology of PKD1, the predominant ADPKD disease gene, and the variable disease severity and age of onset, we aimed to investigate the utility of ExAC for variant assessment in ADPKD. Methods: We assessed coverage and variant quality in the ExAC cohort and combined allele frequency and age data from the ExAC database (n = 60,706) with curated variants from 2000 ADPKD pedigrees (ADPKD Mutation Database). Results: Seventy-six percent of PKD1 and PKD2 were sequenced adequately for variant discovery and variant quality was high in ExAC. In ExAC, we identified 25 truncating and 393 previously reported disease-causing variants in PKD1 and PKD2, 6.9-fold higher than expected. Fifty-four different variants, previously classified as disease-causing, were observed in ≥5 participants in ExAC. Conclusion: Our study demonstrates that many previously implicated disease-causing variants are too common, challenging their pathogenicity, or penetrance. The presence of protein-truncating variants in older participants in ExAC demonstrates the complexity of variant classification and highlights need for further study of prevalence and penetrance of this common monogenic disease.

Original languageEnglish (US)
Pages (from-to)1425-1434
Number of pages10
JournalGenetics in Medicine
Issue number6
StatePublished - Jun 1 2019


  • PKD1
  • PKD2
  • exome sequencing
  • variant interpretation

ASJC Scopus subject areas

  • Genetics(clinical)


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