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Kidney Week

Abstract: FR-PO712

Clinical Whole-Genome Sequencing Enables Diagnostic Certainty in Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Mallawaarachchi, Amali, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  • Hort, Yvonne, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  • Schonrock, Nicole, Genome.One, Sydney, New South Wales, Australia
  • Senum, Sarah R., Mayo Clinic, Rochester, Minnesota, United States
  • Minoche, Andre E., Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  • Hollway, Georgina E., Genome.One, Sydney, New South Wales, Australia
  • Ohnesorg, Thomas, Genome.One, Sydney, New South Wales, Australia
  • Patel, Chirag, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
  • Tchan, Michel, Westmead Hospital, Sydney, New South Wales, Australia
  • Mallett, Andrew John, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
  • Dinger, Marcel E., University of New South Wales, Sydney, New South Wales, Australia
  • Rangan, Gopi, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
  • Cowley, Mark J., Children's Cancer Institute, Randwick, New South Wales, Australia
  • Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
  • Burnett, Leslie, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  • Shine, John, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  • Furlong, Tim, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is predominantly caused by pathogenic-variants in PKD1 or PKD2 and is the most common cause of Polycystic Kidney Disease (PKD). Diagnosis is usually by age-dependent ultrasound criteria, which is challenging in those without family history, with atypical clinical features or younger patients. ADPKD diagnosis has also become more complex with recent identification of additional genes that mimic the phenotype. However, new treatments require definitive diagnosis to appropriately prescribe. Whole Genome Sequencing (WGS) can diagnose PKD, including ADPKD and its gene mimics, and provide prognostic information, but has not been validated for clinical use.

Methods

In this study, we first validated WGS for ADPKD diagnostic testing using a blinded cross-over method. Forty-two adult ADPKD patients underwent sequencing of PKD1 and PKD2 by both WGS and Sanger sequencing. We then examined the first 85 samples referred to a clinically-accredited diagnostic laboratory for WGS, with variant analysis targeted to a PKD gene-panel (PKD1, PKD2, GANAB, HNF1B, PKHD1, UMOD, TSC1, TSC2, OFD1).

Results

WGS identified all PKD1 and PKD2 germline disease-causing variants in the validation study, without false-positive results (sensitivity and specificity 100%). In the unselected, real-world diagnostic cohort (42 males:43 females; median-age 39years (0-79years); 46% with family history of PKD), the overall diagnostic rate was 71%, with a 91% diagnostic rate in patients with typical clinical features of ADPKD (100% with PKD1/PKD2 variants) and 56% in those with atypical clinical features (63% with PKD1/PKD2 variants; 37% with PKHD1, HNF1B, GANAB, TSC2 variants). Most patients with atypical PKD did not have clinical features that predicted likelihood of genetic diagnosis, highlighting the value of genomic testing in this group.

Conclusion

The high diagnostic rate in both typical and atypical PKD suggests clinicians should consider diagnostic genomics in their approach to PKD diagnosis.

Funding

  • Private Foundation Support