Autosomal recessive polycystic kidney disease (ARPKD) and other hepato-renal fibrocystic diseases (HRFD), while relatively rare recessive disorders, constitute an important set of childhood nephropathies. Unlike common disorders, rare disease research requires greater collaboration and centralization of resource collection, e.g. clinical data, bio-specimens (DNA and tissues) and genetic information, because patients are typically limited in number and geographically dispersed. For HRFD, experimental studies would be best served by coordinated case accrual and sharing of clinical and genetic data, as well as bio-specimens.

In the initial Core Center award period (2005-2010), we successfully established the ARPKD Clinical and Genetic Resource to capture clinical and mutational data for ARPKD patients. In the subsequent competitive renewal (2010-present), we have expanded this Core resource to encompass all HRFD, re-developed our Clinical Database using the REDCap platform, and established a human tissue repository. In the proposed competitive renewal, we will continue to compile baseline and longitudinal clinical information in our HRFD clinical database; expand our bio-materials (DNA and tissue) repositories; and deploy new strategies to identify genetic mutations in ARPKD and other HFRD patients, including new tools to interpret PKHD1 missense variants. Clinical and genetic data, as well as patient bio-specimens, will be drawn from tertiary care centers throughout the Americas (North, Central, and South). Finally, we will utilize the learning management system established in our CTSA-funded program to develop a multi-modality resource for expanding our portfolio of HRFD-related educational information and tools. 

Our goal for this renewal application is to acquire a sufficient volume of clinical data, biological specimens, and genomic information in a centralized resource to accelerate discovery research in human HRFD (partnership with Cores B and C) and integrate the resulting data to serve as the foundation for the development of new, targeted interventional strategies (partnership with Core D).

Specific Aims

Aim 1: Expand our knowledge and understanding of HRFD clinical disease, pathology and genetics.

Advanced understanding of the phenotypic and genetic characteristics of HRFD can only be gained with sufficient repositories of clinical cases, as well as biological and genetic samples. We will continue to collect high quality, longitudinal clinical data in our newly re-designed, REDCap-based Database, with the goal of enrolling 50 cases per year. This observational cohort will allow analyses of perinatal morbidity and mortality; characterization of the clinical disease course; correlations between renal and biliary disease progression; and characterization of long-term survivors. In support of Aim 2, we will also request that participants and their parents (patient-parent trios) provide DNA, which will be stored in our CTSA-supported DNA Biobank, with clinical data and DNA samples linked by a unique identifier, which in turn will be linked to biospecimens in the HRFD Tissue Resource via a unique barcode that is assigned to all specimens.

The comprehensive study of recessive HRFD requires adequate supplies of high quality samples from diseased human kidneys, livers and other phenotypically affected tissues. Therefore, we will expand our Tissue Resource to be the largest HRFD tissue repository in the world. All tissues will be assigned a unique bar-coded identifier and subjected to quality control examination. Our target is to collect tissue specimens from a minimum of 10 patients per year.

Aim 2: Identify genetic mutations in ARPKD and other HRFD patients and assess the pathogenicity of sequence variants. 

In partnership with the P50-funded, “Duke Task Force for Neonatal Genomics: Genome and Exome Sequencing and Return of Results” (PI: Nicholas Katsanis), we will use next-generation whole exome sequencing (WES) of DNA collected from patient-parent trios as a first-stage diagnostic tool to identify causative genetic mutations in HRFD patients. We will utilize informatics tools recently developed by our group to assess the pathogenicity of PKHD1 missense mutations. In addition, potential pathological variants in other HRFD genes will undergo functional analyses in the Duke P50 program. A relational database that links clinical and mutational information will be developed and allow accessible linkage to our Investigator User Base in a secure HIPAA-compliant manner.

Aim 3: Establish an annotated, updated, multi-media resource to provide information regarding the diagnosis, management, family impact, and genetics of hepato-renal fibrocystic disease spectrum of disorders, particularly ARPKD.

We will utilize the learning management system established in our CTSA-funded program to develop a multi-modality resource to expand our current portfolio of HRFD-related educational information and tools (http://www.arpkdstudies.uab.edu).