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Kidney Week

Abstract: TH-PO360

PKD1 and PKD2 Copy Number Variations (CNVs) in 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
  • He, Ning, University Health Network, Toronto, Ontario, Canada
  • Khowaja, Saima, 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
  • Pei, York P., University Health Network, Toronto, Ontario, Canada

Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous and primarily due to mutations in PKD1 or PKD2. Although CNVs including genomic deletion/duplication in PKD1 and PKD2 are uncommon, they explain a subset of cases with no mutations detected by NGS studies. Here, we report our results of a CNV screen in a cohort of 1,811 patients from 1,271 different families from eTGESP.


We screened all study patients for PKD1 and PKD2 mutations by targeted NGS and multiplex ligation-dependent probe amplification (MLPA) in NGS mutation-negative cases. Standard algorithms for sequence alignment, base calling, and QC filtering were applied to identify rare (MAF ≤1%) deleterious variants of high and moderate impact as predicted by multiple predictive algorithms. MLPA was performed using two kits (Probemix P351-D1 and P352-E1) from MRC Holland; all detected CNVs were validated by Sanger sequencing and droplet digital PCR (ddPCR) whenever possible.


NGS-based screen failed to detect any definitive PKD1 or PKD2 mutations in 253/1,271 (20%) of families. Follow-up testing with MLPA identified CNVs in 29 of 253 (11.5%) NGS screen-negative families, including 15 with heterozygous PKD1 deletions, 12 with heterozygous PKD2 deletions, and 2 with heterozygous PKD1 duplications; one PKD1 CNV mosiac was also identified.


In this large cohort study from a single geographical region, we found PKD1 and PKD2 CNVs are rare causes of ADPKD, but account for 2.3% (29/1,271) of the entire study cohort and ~10% of our NGS screen-negative families. MPLA provides an important follow-up test for NGS-based PKD1 and PKD2 screen.