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Abstract: SA-PO771

Elucidating the Genetics of Unresolved PKD in a Large Unselected Cohort

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic


  • Moore, Bryn S., Geisinger Health, Danville, Pennsylvania, United States
  • Chang, Alexander R., Geisinger Health, Danville, Pennsylvania, United States
  • Mirshahi, Tooraj, Geisinger Health, Danville, Pennsylvania, United States

We reported on 235 individuals with typical, mild or atypical PKD from an unselected cohort of 174,172 individuals with exome sequencing. Variants in 11 known cystic genes (PKD1, PKD2, ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT140, PKHD1, PRKCSH, and SEC63) were identified in 76.5% of these individuals, leaving 55 with no candidate causal variant.


The 55 individuals with unresolved genetics consisted of 37 with typical, 6 mild and 12 atypical PKD. We expanded the analysis to include 121 cystic genes identified by the Kidney Cystic and Ciliopathy Disorders Gene Curation Expert Panel in an attempt to identify candidate causal variants. Exome sequencing combined with EHR was leveraged to identify rare variants from these genes in these individuals. Variants were evaluated in the general population for cosegregation with disease and evidence of PKD in carriers.


47/55 individuals had at least one rare variant (MAF<0.001) including 13 with protein truncating variants in the 121 genes. Two unrelated individuals, one with mild and one with atypical PKD have the same BICC1 frameshift variant: His141ThrfsTer16 (10:58786953:T:TC). Another with typical PKD is a carrier of two missense variants in BBS2. This individual has several unaffected 1st degree relatives who are carriers of one the variants of BBS2. Additional efforts are underway to determine other candidate variants as well as their penetrance.


Genetic variants in genes other than PKD1 and PKD2 may play a significant role especially in atypical or mild PKD. Exome sequencing in an unselected cohort is a powerful approach to demonstrate the phenotypic and genetic variability of PKD and in determining penetrance.