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Abstract: TH-PO361

Mutation Spectrum of the Extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease (eTGESP)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Haghighi, Amirreza, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • di Bari, Ighli, University Health Network, Toronto, Ontario, Canada
  • Khowaja, Saima, University Health Network, Toronto, Ontario, Canada
  • He, Ning, University Health Network, Toronto, Ontario, Canada
  • Iliuta, Ioan-Andrei, University Health Network, Toronto, Ontario, Canada
  • Song, Xuewen, University Health Network, Toronto, Ontario, Canada
  • Lanktree, Matthew B., St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada
  • Paterson, Andrew, SickKids Research Institute, Toronto, Ontario, Canada
  • Lerner-Ellis, Jordan, Mount Sinai Hospital: Sinai Health, Toronto, Ontario, Canada
  • Pei, York P., University Health Network, Toronto, Ontario, Canada

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease worldwide. Mutations in PKD1 and PKD2, respectively, account for 85% and 15% of the genetically resolved cases in clinical series enriched with high-risk patients. Here, we report the ADPKD mutation spectrum of a large cohort of relatively unselected patients from a single geographical region.


We performed mutation screening in 2,171 patients from 1,606 different families from the Greater Toronto Area (population 6.8 million) using NGS targeted sequencing and multiplex ligation-dependent probe amplification of PKD1 and PKD2, as well as NGS of a panel of 50 cystic disease genes. Standard algorithms for sequence alignment, base calling, and QC filtering were applied to identify rare (MAF ≤1%) deleterious variants as predicted by multiple algorithms.


We detected PKD1 and PKD2 mutations in 1205 (75%) families, non-PKD1 and PKD2 (i.e. ALG8, ALG9, PKHD1, GANAB, PRKCSH, SEC63, LRP5, WFS1, TSC1-2, COL4A1, and COL4A3-5) rare putative pathogenic variants in 120 (10%) families, with no mutations detected in 281 (15%) families. Among the PKD1 and PKD2 genetically resolved families, 916 (76%) and 289 (24%) were due to mutations in PKD1 and PKD2, respectively. Adjusted for exon size across all 46 exons in PKD1, we found an enrichment of truncating mutations in exon 44. We also found over 100 recurrent mutations in ≥ 2 different families (haplotype analysis is in progress).


We found extensive genic and allelic heterogeneity in ADPKD with a higher prevalence of PKD2 mutations than reported in the clinical series. We also found non-PKD1 and non-PKD2 cystic disease mutations in 10% of families, while 15% of the families remained genetically unresolved.

Recurrent PKD1 and PKD2 Mutations
Gene NameNumber of different pathogenic mutationsNumber of pathogenic mutations in ≥ 2 different familiesNumber of pathogenic mutations in ≥ 3 different families