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Kidney Week

Abstract: SA-PO772

Complex Genetic in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic


  • Dehkharghanian, Taher, University Health Network, Toronto, Ontario, Canada
  • Miranda Cam, Mauricio Alejandro, University Health Network, Toronto, Ontario, Canada
  • Haghighi, Amirreza, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Carriazo Julio, Sol Maria, University Health Network, Toronto, Ontario, Canada
  • Khowaja, Saima, University Health Network, Toronto, Ontario, Canada
  • Song, Xuewen, University Health Network, Toronto, Ontario, Canada
  • Lanktree, Matthew B., Saint Joseph's Healthcare Hamilton - Charlton Campus, Hamilton, Ontario, Canada
  • Paterson, Andrew, SickKids Research Institute, Toronto, Ontario, Canada
  • Pei, York P., University Health Network, Toronto, Ontario, Canada

ADPKD is genetically heterogeneous and primarily due to mutations in PKD1 or PKD2. Complex inheritance with biallelic PKD1 or digenic PKD1 and PKD2 mutations (a.k.a. complex genetic) has been reported in a small number of families. Here, we report the prevalence and genotype-phenotype correlation of patients with complex genetic from the extended Toronto Genetic Epidemiology Study of PKD.


All study patients underwent PKD1 and PKD2 mutation screening by targeted Next-Generation sequencing (NGS) and multiplex ligation-dependent probe amplification in 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. Patients with complex genetic were defined as those with two pathogenic mutations in PKD1, or in PKD1 and PKD2. Phase was determined in all patients with PKD1 biallelic mutations.


We found genetic complexity in 47/993 (4.7%) of families with an identifiable PKD1 or PKD2 mutations. Preliminary results from 44 of 53 patients in these families suggest that patients with a protein-truncating (PT) and a non-truncating (NT) PKD1 mutation have more severe disease (by eGFR and TKV; see figure) than patients with two PT-PKD1 mutations in-cis, two NT-PKD1 mutations in-trans, or PKD1 and PKD2 digenic mutations.


In this large cohort study from a single geographic region, we found that patients with genetic complexity in ~5% of families with a known PKD1 or PKD2 mutation. Delineating complex genetic by NGS has important implications for genetic counselling and may improve clinical prognostication in ADPKD.


  • Government Support – Non-U.S.