ADPKD: Disease Spectrum & Genotype-Phenotype Correlations

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DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic disorders (1:400-1000) and an important cause of end stage renal disease (ESRD). In the US in 2012, ~30,000 patients had PKD associated ESRD; 1/3500 individuals aged 65-69y. The disease is generally late in onset, but considerable variability exists, from in utero onset and perinatal death, early onset (EO) disease, to adequate renal function into old age. Extrarenal manifestations, particularly a higher incidence of intracranial aneurysms (ICA) and severe polycystic liver disease (sPLD) are associated with morbidity and mortality. The overall goal of this proposal is to determine the extent to which genetic factors at the two known genes, PKD1 (16p13.3) and PKD2 (4q21) and elsewhere in the genome, determine the severity of renal disease and the occurrence of clinically significant extrarenal complications. These studies are based upon our findings, and those of others that genic, allelic and genetic background effects significantly influence the phenotype. Next generation sequencing (NGS) will be employed for mutation screening of the ADPKD genes, including the duplicated PKD1, necessitating enrichment by locus specific long-range PCR (LR-PCR). Mutations and variants elsewhere in the genome will be identified employing custom-made panels of candidate genes (HaloPlex methodology) and whole exome sequencing (WES). Aim 1 will screen the ADPKD genes to identify atypical mutations in the 7-10% of patients that are presently unresolved, and assess the role of allelic combinations as pathogenic events, especially causing EO disease. Aim 2 will analyze a large, typical ADPKD population and ones with the vascular and sPLD phenotype to determine the full role that ADPKD genic and allelic effects play in accounting for phenotypic variability. Aim 3 will screen loci beyond the ADPKD genes, including the whole exome, for novel causative genes resulting in an ADPKD-like phenotype. Aim 4 will analyze the whole exome for modifying factors that cause EO disease and clinically significant vascular and hepatic complications. The final aim will test the significance of putative pathogenic ADPKD alleles in vivo, analyzing the mechanisms of pathogenesis and optimizing mouse models for preclinical testing. Overall these studies will better explain the genetic causes of ADPKD, provide insights into the pathogenesis, possibly revealing novel therapeutic targets, optimize models for preclinical testing, be of diagnostic and prognostic value, and identify populations suitable for clinical trials and that will gain most fro disease-specific therapeutics which will be available soon.