Danny E. Miller: Sequencing resolves complex SVs and identifies missing pathogenic variants in u...

Despite recent advances in genetic testing, many individuals with inherited bleeding disorders remain unsolved after a complete clinical evaluation. In some cases, no variant is found in a particular gene or genes of interest, while in other cases a large structural variant (SV) is found or suspected that cannot be resolved using existing methods. In MyLifeOurFuture, a large U.S. hemophilia genotyping initiative, approximately 2% of participants with hemophilia A had no F8 variant identified despite exhaustive investigation. Additionally, large SVs were common in severe hemophilia and associated with inhibitor risk but were incompletely characterized in nearly all cases. We hypothesized that long-read sequencing would identify missing diseasecausing variants and fully characterize SVs associated with hemophilia in these individuals.