By Andreas Scherer, PhD, Founder and CEO, Salto Partners
Short-read sequencing remains the workhorse of clinical genomics: accurate, affordable and deeply embedded in diagnostic pipelines. Long-read sequencing is not its replacement. Its strategic value is closing the gaps short reads cannot.
The core argument
- Known blind spots. Pseudogenes and segmental duplications (PMS2, SMN1/SMN2, CYP2D6), large structural variants, repeat expansions, deep intronic variants and methylation all challenge short-read workflows.
- One assay instead of several. Long reads can size a repeat expansion and read its methylation status in a single step, for example in FMR1 or DMPK, where labs today often run multiple tests.
- Phasing matters clinically. Knowing whether variants sit on the same or opposite chromosome changes risk assessment and pharmacogenomic calls.
- The future is hybrid. Most labs will keep short reads for routine volume and add long reads where precision matters more than throughput.
What it means for leaders
Buying an instrument is the smallest part of the decision. A hybrid lab needs informatics that normalizes both data types into one interpretation and reporting flow, handles new variant classes, and keeps every result traceable. It also needs validation and quality documentation for those new variant classes, under CLIA and CAP in the U.S. and IVDR in Europe.
The practical path is to start in high-value niches, such as unresolved hereditary cancer cases, repeat expansion disorders and complex pharmacogenes, then expand as costs fall and evidence grows. Cross-train staff early. Whether long reads end up at 5 percent or 50 percent of case volume, the labs that prepared their infrastructure first will capture the value.
Read the full perspective: Long-Read Sequencing in the Clinic: A Strategic Inflection Point, published in GenomeWeb.
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