Long-Read Genome Sequencing Outperforms Standard Tests for Rare Disease Diagnosis

Researchers at Radboud University Medical Center have published a practical demonstration that clinical long-read genome sequencing (lrGS) can diagnose more patients with rare genetic diseases than the current standard-of-care, potentially solving a decades-long diagnostic deadlock. The study, published on June 13 in the New England Journal of Medicine, positions the test as a single, comprehensive replacement for up to 15 existing tests and recommends global adoption as the first-choice diagnostic .

Approximately 400 million people worldwide are affected by over 7,000 rare diseases, yet more than half remain undiagnosed after standard genetic testing . The Radboud study addresses this gap directly by offering a single, more powerful test that consolidates what previously required a battery of separate tests into one streamlined workflow .

How the new test works

Long-read sequencing reads continuous DNA segments of 15,000–20,000 base pairs, roughly 100 times longer than the current short-read standard of 150–300 base pairs . This longer read length allows the technology to resolve complex genomic regions, repetitive sequences, and large structural rearrangements that short-read methods cannot map accurately .

As a bonus, the platform captures epigenetic modifications, such as DNA methylation, directly from the same sequencing run, adding a layer of functional genomic information without requiring a separate test .

The diagnostic yield improvement

In a prospective study of 832 patients presented at ESHG 2026, long-read genome sequencing delivered a conclusive diagnosis for 160 patients (19.2%), compared to 137 patients (16.5%) for standard-of-care testing, a net absolute increase of 2.7 percentage points, equating to roughly 3% more diagnoses .

Earlier, separate research in already-undiagnosed cohorts reported additional diagnostic yields of 7–17% after negative short-read genome sequencing . While the gain in this particular head-to-head study appears modest, it is clinically meaningful because it occurs on top of already-optimized standard testing, closing an important diagnostic gap for patients who would otherwise remain without an answer.

Replacing a battery of tests with a single assay

Standard diagnostic workflows for rare diseases often rely on a cascade of separate tests, each designed to detect a different class of genetic variant. The new long-read test can replace up to 15 of those existing tests, detecting single-nucleotide variants (SNVs), small insertions and deletions (indels), structural variants, short tandem repeat expansions, and complex rearrangements all in one assay .

Radboud UMC has already implemented the test in routine clinical practice, planning to run up to 5,000 tests per year. HiFi whole genome sequencing matched standard-of-care testing with 96.4% concordance across variant types, and modeling across an annual patient population suggested it could refine or improve diagnostic findings in an estimated 3.4% of cases .

Why it matters globally

Professor Lisenka Vissers and colleagues recommend that long-read sequencing be adopted worldwide as the first-choice diagnostic for rare genetic disorders. The reasoning is practical: one test that is faster, more comprehensive, and more efficient than the current patchwork of sequential testing can shorten the diagnostic odyssey for patients and families who often wait years for an answer .

The study is not speculative. It validates a technology already live in a clinical laboratory, at scale, and presents evidence that the transition from multiple tests to a single long-read workflow is feasible for other centers. The broader hope is that routine use will gradually shrink the enormous diagnostic gap that has persisted even with the widespread availability of short-read exome and genome sequencing .