Center for Modeling Non-Coding Disease Variants: Preclinical/Co-Clinical Core

PROJECT SUMMARY/ABSTRACT: PRECLINICAL/CO-CLINICAL CORE Mendelian conditions, in which variation of a single gene drives the disease phenotype, are a major disease burden causing suffering and taxing the healthcare system. In recent years, increasing accessibility of exome and genome sequencing has led to rapid increase in the number of gene-disease associations. Although these advances have led to answers and treatments for many families with Mendelian diseases, 60-80% of cases with a suspected genetic etiology remain unsolved. Current analysis strategies are optimized to find small coding and splice junction variants but can be insensitive for non-coding and structural variants. While many bioinformatic pipelines can robustly call non-coding variants, our ability to attribute them to Mendelian diseases is limited by the paucity of data on their biological function. As a result, non-coding variants detected on clinical genomic tests are often either filtered out due to inability to determine their consequence or reported to the clinician as variants of uncertain significance. This knowledge gap limits our ability to diagnose conditions caused by non-coding variants and identify biomarkers for variant resolution and therapy-development. A collaborative center to model the impact of non-coding variants will accelerate the pace of disease-gene discovery, elucidate the disease physiology, and identify molecular phenotypes that can be used as biomarkers for disease diagnosis and to develop therapeutic interventions. Our proposal leverages the broad clinical and research expertise of existing UCI rare-disease genomics programs to create a Co-Clinical Core supporting a center for modeling non-coding variants in rare disease. This core will collect high quality phenotype data to support variant prioritization and analysis, collect human tissues for preclinical studies and storage, and facilitate return of results and future collaboration. This collaborative approach will allow for integration of clinical and research grade human data with data from cell and animal models to facilitate the discovery, diagnosis, and understanding of non-coding disease variants. The core will function locally as well as globally as part of a network of precision modeling centers to collect standardized data and contribute to network-wide protocols.