Hypothetical incorporation of LRS into the undiagnosed RD care pathway. (Left) The current care pathway in which patients with RDs may undergo long diagnostic odysseys, receiving numerous different consecutive genomic tests depending on indications, including genome-wide SRS. (Middle) Proposed incorporation of LRS as a second-tier test following nondiagnostic genome-wide SRS testing. Studies support an increased diagnostic yield when incorporating LRS following genome-wide SRS; therefore, this pathway has the potential to reduce the number of patients with undiagnosed RDs. (Right) Proposal for incorporating LRS as a first-tier test in the future, which would be primarily useful for RDs in which LRS first may be most cost-effective. This reduces the step-wise diagnostic pathway but allows for consecutive analyses of LRS data (e.g., coding variation, repeat expansions, SVs, methylation).
