Clinical Long-Read WGS Shows Diagnostic Potential, Faces Cost Challenges

TAIPEI, TAIWAN, Oct. 2nd, 2025- Clinical long-read whole-genome sequencing (WGS) is emerging as a potential replacement for multiple genetic testing methods in pediatric diagnostics. A recently published study highlights both the promise of this approach and the practical hurdles that still limit its widespread clinical use.

The study analyzed 235 patient cases with long-read WGS and compared outcomes to 513 historical controls matched by age, sex, and clinical indication. Long-read WGS increased the diagnostic yield to 37 percent, compared with 27 percent using conventional methods such as gene panels, cytogenetics, microarrays, and exome sequencing. It also shortened average turnaround times: 27 days to reach a diagnosis versus 62 days with standard tests, and 29 days to a negative result versus 91 days.

Of the cases where a diagnosis was achieved, 16 of 87 depended on features unique to long-read sequencing. These included detecting rare repeat expansions, structural variants, aberrant methylation, and phase single-nucleotide variants—insights often missed with short-read technologies. For conditions such as hypotonia, which may be caused by a wide range of genetic factors, the ability to consolidate multiple tests into a single comprehensive analysis is particularly advantageous.

Despite these strengths, the study also pointed to barriers that could hinder broader adoption. Cost remains the most significant challenge, with sequencing reagents for long-read WGS costing more than twice as much as those for short-read sequencing. Interpretation of results is also complex, as most clinical software tools are designed for short-read data. Specialized or custom-built software is still required for certain variant types, such as methylation or structural changes.

Turnaround time presents another consideration. While the fastest result in the study was achieved in 14 days, rapid short-read WGS or other long-read approaches can return answers in just a few days. Although new protocols and improved sequencing reagents have enhanced performance, workflows remain slower than the most rapid alternatives.

Overall, the findings underscore the potential of long-read WGS to provide richer genomic insights, particularly for complex cases where conventional testing may fall short. However, widespread clinical adoption will depend on further reductions in cost, more user-friendly interpretation software, and greater acceptance among physicians and healthcare payors.

For now, clinical long-read WGS remains a promising but still evolving technology that could transform genetic diagnostics if economic and practical barriers can be addressed.

References:

[1] Clinical Long-Read WGS Challenges, Abilities Highlighted in New Study

[2] Children's Mercy Clinical Validation of Long-Read WGS Assay Sets Stage for Frontline Evaluation

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