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Abstract: TH-PO662

Performance of Targeted Cystogene Next Generation Sequencing in an ADPKD Population with CKD

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Senum, Sarah R., Mayo Clinic , Rochester, Minnesota, United States
  • Baheti, Saurabh, Mayo Clinic , Rochester, Minnesota, United States
  • Cornec-Le Gall, Emilie, Centre Hospitalier Universitaire de Brest, BREST, France
  • Torres, Vicente E., Mayo Clinic , Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Clinic , Rochester, Minnesota, United States

Next generation sequencing (NGS) panels containing all genes in a disease category can provide high throughput, comprehensive coverage with a single screen, be cost effective, have high diagnostic efficiency, and provide information about possible disease modifiers. Mutation data in ADPKD is increasingly being recognized for its diagnostic and prognostic value. However, screening ADPKD populations is complicated by genic and extreme allelic heterogeneity, segmental duplication of PKD1 with six pseudogenes sharing >97% sequence similarity with PKD1, and several GC rich regions.


The screened ADPKD patients had impaired renal function but without ESRD. Samples were screened using an NGS panel containing 136 known or candidate renal cystic or ciliopathy genes. Read alignment and variant calling were performed using the Genome Analysis Toolkit, and LOG2 ratio data was generated to assess for large deletions or duplications. Variant mining was performed with Golden Helix SNP & Variation Suite. Predicted pathogenic base pair variants were confirmed by Sanger sequencing with Multiplex Ligation-dependent Probe Amplification (MLPA) employed to confirm large rearrangements.


A >40x read depth was obtained for 96.80 ± 0.14% (95% CI) of the 683kb target region, although lower coverage of particularly GC rich regions of PKD1 was found. Of 384 cases with complete analysis, 187 (48.7%) were PKD1 truncating, 98 (25.5%) PKD1 non-truncating, and 63 (16.4%) PKD2. The pathogenic variants included 11 large deletions (8 in PKD1 and 3 in PKD2) and 2 large duplications (PKD1) detected by CNV analysis. The 36 (9.4%) unresolved cases, including some with PKD1 and PKD2 variants of uncertain significance, are being rescreened by the conventional LR-PCR/Sanger approach to determine if specific mutations were missed. Genic and allelic complexity is also being assessed in these cases.


Targeted NGS identifies PKD1 and PKD2 pathogenic variants nearly as effectively as cumbersome LR-PCR/Sanger approaches. Detailed analysis of negative cases will detect screening deficiencies and highlight possible improvements to the panel design.


  • NIDDK Support