Center for Integrated Approached to Undiagnosed Diseases

项目总结

PROJECT SUMMARY Undiagnosed diseases are likely to be determined by genetic, environmental, and developmental factors. While some undiagnosed diseases will represent novel rare genetic syndromes with monogenic or oligogenic etiologies and others will reflect rare manifestations of known diseases, many are likely to result from a more analytically challenging combination of multiple genetic, environmental, and developmental factors. Whole exome and whole genome sequencing are powerful tools with which to ascertain the genetic contributions to undiagnosed diseases; however, these methods alone are unlikely to elucidate the basis for many, if not most, undiagnosed diseases. Using an integrated, network-based, systems biology approach that incorporates not only genetic variation data, but also gene expression, metabolomic, proteomic, and exposomic data, along with careful deep phenotyping, has shown to be the most effective way to identify the pathways and mechanisms responsible for many undiagnosed diseases. We will continue our integrated interdisciplinary research plan for the Harvard Undiagnosed Disease Network Clinical Site (Harvard UDN-CS) that involves three Specific Aims: 1) Ascertainment and clinical characterization - we will perform case ascertainment and phenotypic characterization for selected rare and undiagnosed disease states in adults and children; 2) Genomic assessments - we will use patient and family member-derived DNA sequence, transcriptomic data, and clinical phenotype information to identify potentially causal DNA sequence variants, gene expression variation, and potentially causative pathway derangements; and 3) Network approach to disease diagnosis - we will integrate other -omic data, including metabolomic, proteomic, and exposomic data, along with the candidate genetic variants into the comprehensive interactome, and thereby identify diseases or disease pathways in network proximity to the involved genes that may help identify potential pathobiological modules relevant to the etiology of the undiagnosed disease. For probands accepted on or before June 30, 2022, this supplement will allow us to continue our work toward meeting these specific aims and addressing the overall hypothesis in close collaboration with the UDN Coordinating Center (UDN-CC) and other clinical sites in the UDN in order to develop and implement assessment protocols of phenotype, environment, and genotype that will ultimately define the etiology and treatment of undiagnosed diseases.