Abstract: FR-PO328

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

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Haghighi, Amirreza, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
  • Pei, York P., University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Song, Xuewen, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Pourafkari, Marina, University Health Network, Toronto, Ontario, Canada
  • Shi, Beili, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Cornec-Le Gall, Emilie, Mayo Clinic, Rochester, Minnesota, United States
  • He, Ning, University Health Network and University of Toronto, Toronto, Ontario, Canada
  • Cnossen, Wybrich Riemke, Radboud University Nijmegen Medical Center, Nijmegen, Gelderland, Netherlands
  • Drenth, Joost P.H., Radboud University Nijmegen Medical Center, Nijmegen, Gelderland, Netherlands
  • Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
Background

Severe PLD 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 imparing 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.

Methods

We performed whole exome sequencing (WES) using Illumina HiSeq2000/2500 with SSV4/5 capture kit in 150 patients including 23 affected discordant sib-pairs and 10 affected concordant sib-pairs for sPLD from 33 families (matched by gender and age) and 83 sporadic cases. All patients with sPLD had a cystic liver of >4x normal volume. In addition to a focused analysis on 166 genes involved in ER-PP pathway, we also performed a genome-wide analysis. 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, Mutation Assessor, Mammalian and Vertebrate nucleotide-level conservation, and Combined Annotation Dependent Depletion (CADD).

Results

Overall, we achieved a mean target coverage of 108X with 90% of the targeted exomes having >30X read depth. In our preliminary analysis, we identified a total of 4,696 rare deleterious variants that segregated with PLD disease severity in at least one family. We found 8 ER-PP genes (i.e. WFS1, UGGT1, UGGT2, SEC24D, SEC23B, EIF2AK4, ATF6B and RPN1) with rare deleterious variants that segregated in at least one family and 3-4 sporadic sPLD cases. We also identified 7 non ER-PP genes (i.e. TTN, DNAH10, DNAH14, HMCN2, NEB, OBSCN and ADAMTS8) with rare deleterious variants that segregated in 4 to 6 families each.

Conclusion

Our preliminary 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.

Funding

  • Private Foundation Support