NCM 2022: Long-read sequencing resolves complex structural variants and identifies missing pathogenic variants in unsolved hemophilia cases

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. haemophilia genotyping initiative, approximately 2% of participants with haemophilia A had no F8 variant identified despite exhaustive investigation. Additionally, large SVs were common in severe haemophilia and associated with inhibitor risk but were incompletely characterised in nearly all cases. We hypothesised that long-read sequencing would identify missing disease-causing variants and fully characterise SVs associated with haemophilia in these individuals.