Current position in this corpus
Long-read WGS adds the most diagnostic value in rare disease when the likely mechanism involves structural complexity, dead zones, phasing problems, methylation, or hard-to-map medically relevant genes.
Strong supporting sources
Working synthesis
- Targeted use is strongly supported for immunodeficiency-like dead-zone cases, structurally complex CNV cases, and unresolved rare disease cases after negative short-read testing.
- A broader unified-platform argument is also supported, especially when long-read WGS can replace multiple follow-up assays by combining small variants, SVs, phasing, and methylation.
- Population SV resources appear increasingly useful as filtering aids in rare disease interpretation.
Main tension
- Kobayashi 2022 supports selective deployment.
- Sinha 2025 supports broader clinical deployment of one long-read workflow.
Open questions
- Which phenotype classes should be first-line candidates for long-read WGS?
- How much additional yield comes from methylation, phasing, and SV detection separately?