identifying GENetic factOrs influencing the development of VAScular aneurysms in autosomal dominant Polycystic Kidney Disease – GENOVAS-PKD

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, with an estimated prevalence of ~1 in 1000 to 1 in 2500 individuals. Its course is characterized by the development of multiple kidney cysts, causing progressive loss of kidney function and frequently leading to end-stage kidney disease during or after the sixth decade. The most severe extra renal manifestation in ADPKD is the development of intracranial aneurysm (IA). IA prevalence is fivefold higher in ADPKD than in the general population, with estimates ranging from 9 to 12%. The main complication of IAs is subarachnoid hemorrhage following rupture, with a mean age of 41 years in ADPKD patients versus 51 years in the general population, and a high rate of mortality and morbidity. The only identified risk factor for IA in ADPKD is a familial history of unruptured or ruptured IA, with a prevalence of 22% in patients with a familial risk of IA, versus 6-8% in the absence of family history. Until now, despite strong familial clustering of IA cases in some ADPKD pedigrees, no genetic factor associated with the development of IA has been identified. Indication, timing, and frequency of IA screening in ADPKD patients are not well defined. In this translational research project, we aim to identify the genetic determinants of IA formation in ADPKD patients. The GENOVAS-PKD study will take advantage of international and local ongoing collaborations, allowing us to gather the largest cohort of ADPKD patients affected by IA worldwide. We will evaluate the respective influences of genetic and non-genetic risk factors, and revisit the genic and allelic influence of the ADPKD genes on IA risk. We will perform whole exome-sequencing in informative pedigrees and in a large cohort of unrelated ADPKD individuals with a past history of IA to identify candidate genes, and we will employ targeted next-generation sequencing to analyze these candidate genes in a large replication cohort. We will develop first-line functional assays to understand the pathogenic mechanisms resulting from the variants identified. Through the identification of genes influencing the development of IA in ADPKD patients, our hope is to improve the pre-symptomatic screening strategy, which will alleviate the mortality and morbidity burdens associated with this severe complication. Understanding the genetic determinants of IA formation will provide a better understanding of IA pathogenesis, hopefully translating into the discovery of pathways amenable to disease-modifying therapies.