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Abstract: TH-PO671

Identifying Genetic Modifiers in Severe Polycystic Liver Disease (PLD) by Whole Exome Sequencing

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Haghighi, Amirreza, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Song, Xuewen, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Cornec-Le Gall, Emilie, Centre Hospitalier Universitaire de Brest, BREST, France
  • Demoulin, Nathalie, Cliniques U St-Luc, Brussels, Belgium
  • Cnossen, Wybrich Riemke, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
  • Hoenderop, Joost, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
  • Devuyst, Olivier, University of Zurich, Zurich, Switzerland
  • Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
  • Pei, York P., University Health Network and University of Toronto, Toronto, Ontario, Canada

Severe PLD (sPLD) is a rare and poorly understood phenotype seen in both ADPKD and ADPLD.
Mutations of SEC61, SEC63, PRKCSH, GANAB, and ALG8 have been shown to cause PLD by impairing the maturation and transit of polycystin-1 (PC1) through the endoplasmic reticulum protein-processing (ER-PP) pathway. We hypothesize that rare mutations including ER-PP pathway genes that segregate in multiple families may modify PLD in patients with ADPKD and ADPLD.


We performed whole exome sequencing (WES) using Illumina HiSeq2000/2500 with SSV4/5 capture kit in 203 patients from Canada, U.S., Belgium, and the Netherlands, including 23 affected discordant sib-pairs and 16 affected concordant sib-pairs for sPLD from 39 families (matched by gender and age) and 125 sporadic cases. All patients with sPLD had a cystic liver of >4x normal volume. We performed a focused analysis on 168 genes involved in ER-PP pathway. 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 PolyPhen-2, SIFT, PROVEN, Mutation Tester, Mutation Assessor, Mammalian and Vertebrate nucleotide-level conservation, and Combined Annotation Dependent Depletion.


Overall, we achieved a mean target coverage of 99X with 90% of the targeted exomes having >30X read depth. We identified 123 ER genes with rare deleterious variants and among them, we found 9 ER genes (i.e. UGGT1, UGGT2, SEC31B, SEC24D, SEC23B, ALG8, ALG6, PRKN and ATF6B) with rare high and/or moderate impact variant(s) present in more than 6 subjects and each segregated with PLD disease severity in 1 to 4 families and 4-10 sporadic sPLD cases.


Our results suggest extensive genetic heterogeneity with no one single gene accounting for a large proportion of severe PLD cases. Future in-vitro and/or in-vivo functional studies will be needed to define the potential pathogenicity of the most promising candidate genes. Identification of genetic modifiers of severe PLD has the potential to improve risk prediction and treatment of this unusual complication.


  • Private Foundation Support