Approved research

Genetic causes of polycystic kidney disease

Lay summary

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by progressive loss of renal function due to the formation of fluid-filled cysts in the renal parenchyma and is the most common monogenic kidney disease. ADPKD patients progress to end stage renal disease in the 5th to 7th decade of their lives. Among ADPKD patients, ~90% have pathogenic genetic mutations in two genes: PKD1 or PKD2. The remaining 10% of ADPKD patients have genetic mutations in several other genes, 7 of which have been identified and other genes that are yet to be identified. We have leveraged over 90,000 whole exome sequences (WES) linkable to electronic health records (EHR) in the Geisinger-MyCode DiscovEHR cohort to determine penetrance of variants of PKD1 and PKD2 and identify genes whose variants contribute to ADPKD. The aim of the current proposal is twofold: first, to replicate our findings in our cohort and improve upon our understanding of the penetrance of PKD1/2 mutations in ADPKD; second, to find novel mutations in other genes that may lead to ADPKD and therefore improve our understanding of genetically unresolved ADPKD. Tolvaptan is a V2R antagonist that has been approved for treatment of ADPKD-a greater understanding of the genetics and progression of ADPKD will help provide better early treatment options and additional preventive measures that may delay the onset of ESRD in ADPKD patients.