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Kidney Week

Abstract: FR-PO711

Diagnostic Utility of Whole-Exome Sequencing in Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Chang, Alex R., Geisinger Medical Center, Danville, Pennsylvania, United States
  • Abdalla, Yoosif, Geisinger Medical Center, Danville, Pennsylvania, United States
  • Taher, f m, Geisinger, Danville, Pennsylvania, United States
  • Luo, Jonathan Z., Geisinger, Danville, Pennsylvania, United States
  • Mirshahi, Tooraj, Geisinger Clinic, Danville, Pennsylvania, United States

Whole exome sequencing (WES) is increasingly being used to screen for certain genetic conditions, including some genetic forms of kidney disease. However, there are challenges in sequencing adult polycystic kidney disease (ADPKD) due to PKD1 having 6 pseudogenes. Our goal was to examine WES accuracy in individuals with clinical diagnosis of ADPKD, as well as in an unselected cohort.


We examined data from 31,391 subjects in the Geisinger-MyCode population as part of the Regeneron-DiscovEHR collaboration. WES was performed using a modified version of the IDT xGen Exome Research Panel. Average depth of coverage for PKD1 and PKD2 were 27X and 33X, respectively. We identified subjects with PKD1 or PKD2 putative loss-of-function (pLoF) mutations (stop-gain, frameshift, canonical splice) as well as large deletions encompassing PKD1or PKD2 detected in WES-based CNV analysis. ADPKD phenotyping was done by identification of individuals who had a diagnosis code for polycystic kidney disease, followed by confirmation by chart review.


Out of the 31,391 subjects, we identified 22 (0.07%) patients with clinical diagnosis of ADPKD using a phenotype-first approach, and 26 (0.08%) pLOF mutation carriers using a genotype-first approach. With a phenotype-first approach, we found pLOF mutations in 21/22 (95.5%) patients with clinical diagnosis of ADPKD (13 PKD1 and 8 PKD2 carriers). Of the 26 pLoF carriers, there were 18 PKD1 carriers and 8 PKD2 carriers. All 8 PKD2 carriers had clinical diagnosis of ADPKD by chart review. Of the 18 PKD1 carriers, 12 had ADPKD by chart review although 2 of the remaining 6 patients without evidence of ADPKD were in their 30s and lacked adequate abdominal imaging.


When conducted with a sequencing platform that achieves sufficient depth of coverage of PKD1, WES provided 100% diagnostic accuracy in PKD2 pLoF carriers and showed high sensitivity but limited specificity for PKD1 pLoF carriers. WES may have diagnostic value in a genotype-first approach in identifying ADPKD patients, but additional confirmation of PKD1 mutations may be needed.


  • NIDDK Support