PROJECT SUMMARY Research on structural variants (SVs) has elucidated their importance to medicine and molecular biology, establishing their roles in regulation of gene expression, implications in diseases, and ethnic diversity. While large-scale studies of SVs have catalogued extensive variation in global populations, those found are often of unknown consequence in terms of what products they produce and what potential biological effects they may cause. In parallel, we and others have discovered a large number of chimeric RNAs in diseased and normal physiological tissues and cells. A subset of these RNA fusions are a consequence of SVs, which we call them canonical chimeric RNAS differentiating from the non-canonical chimeric RNAs made by intergenic splicing. We have therefore developed a bottom-up approach, using chimeric RNAs found in the GTEx dataset, to the identify SVs which produce gene fusion transcripts. These are therefore enriched for functionality and phenotypic impacts over traditional SV prediction methods, which catalogue SVs as polymorphisms. Each can be used as basis for PheWAS to find associated clinical variables or patient characteristics, and can serve as easily detectable biomarkers for personalized medicine. In our preliminary study, we uncovered over 90 such chimeric RNAs and their associated SVs, 42 of which have been predicted in whole blood or lymphocytes, which further supports their accessibility as biomarkers. One such chimeric RNA], SUZ12P1-CRLF3, is the result of a complex rearrangement on 17q11.2 and presents in individuals with African ancestry. The parental genes lie within a region deleted in a subset of type 1 neurofibromatosis (NF1) patients, and the rearrangement itself, intersects with known breakpoint deletions. We have observed from our limited clinical data that this chimeric RNA (and SV) is associated with acute cerebrovascular disease and smaller stature, and also exhibits a weaker association with gastrointestinal hemorrhage, all of which are indications of NF1. We plan to leverage the rich set of genomic and clinical data in All Of US program to achieve the following two goals. Aim1, Utilize the All of Us cohort to assess associations of the SUZ12P1-CRLF3 chiRNA with donor phenotypes, including NF1 and other clinical parameters. Aim2, Perform PheWAS on the remaining 92 canonical chimeric RNAs and their associated SVs. The findings will not only validate our bottom-up approach in identifying functional SVs, but also lead to novel clinical insights on a large number of novel SVs.