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Abstract: TH-PO362

Families With Complex Genetics in 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
  • 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. Complex inheritance with bilineal disease arising from two independently segregating PKD1, or PKD1 and PKD2 mutations have been reported in a small number of families. Here, we define the prevalence and clinical features of ADPKD families with complex genetics in 1,811 patients from 1,271 different families from eTGESP.


All study patients underwent PKD1 and PKD2 mutation screening by targeted Next-Generation sequencing and multiplex ligation-dependent probe amplification in mutation-negative cases, as well as targeted NGS with a cystic disease panel of 50 genes. 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. Families with complex genetics were defined as those with two putative pathogenic mutations in PKD1, in PKD1 and PKD2, or in PKD1 or PKD2 with another non-PKD1 and non-PKD2 cystic disease mutation.


We found complex genetics in 71/993 (7.2%) of genetically resolved families. Among the families with complex genetics, 48 (68%) carried two PKD1 mutations, 5 (7%) carried both a PKD1 and PKD2 mutation, and 18 (25%) carried either a PKD1 or PKD2 mutation with a second mutation in other cystic disease genes (i.e. ALG8, ALG9, PKHD1, PRKCSH, SEC63, WFS1, and COL4A5). Analyses of phenotype-genotype correlations in these families are currently in progress.


Gene locus and allelic heterogeneity have been shown to account for a significant proportion of disease variability in ADPKD. Here, we found complex genetics in 7% of a large cohort of families harboring two cystic disease mutations; the presence of a second mutation may potentially act as a modifier of the main effect mutation and contributes to the within-family disease variability.