Long-Read DNA Test Improves Diagnosis of Rare Genetic Diseases

Rare diseases affect up to 400 million people worldwide, yet many remain difficult to diagnose and often require years-long diagnostic journeys. Approximately 80% have a genetic basis, but conventional tests analyze the genome in fragments and can miss complex variants. These limitations can delay care planning and family risk assessment across more than 7,000 conditions. A new study shows that a comprehensive long-read DNA test increases diagnostic yield and could streamline the diagnostic workup.

Radboud University Medical Center (Radboudumc; Nijmegen, Netherlands) and Maastricht University Medical Center+ (Maastricht UMC+) evaluated a long-read genome sequencing test alongside current standard diagnostics in 1,000 patients. The team found the approach delivered additional answers and could simplify multi-test pathways for rare genetic disorders. Writing in The New England Journal of Medicine, the researchers recommend that this test be adopted everywhere as the first-choice diagnostic.

The method reads DNA in much larger segments—up to 20,000 building blocks—compared with today’s typical fragment length of about 300. Like assembling a jigsaw puzzle, using larger pieces makes reconstruction easier and yields a more complete picture of the genome. The test also measures modifications on the outside of DNA that can switch genes on or off, capturing information that otherwise requires extra specialized tests.

In the head-to-head comparison, the new test produced 3% more diagnoses than standard workflows. It can also replace 15 other tests, reducing the need for multiple procedures while improving diagnostic efficiency. The number of diagnoses is expected to continue rising as more complex and difficult-to-detect abnormalities are linked to specific conditions.

Use of long-read sequencing was further highlighted at the recent Undiagnosed Hackathon in Nijmegen. Nearly 150 specialists from all Dutch university medical centers analyzed 33 families, and the long-read approach mapped each family’s DNA in detail. The effort resulted in five new diagnoses, underscoring the test’s ability to reveal clinically relevant findings.

“We showed that the new test yields 3% more diagnoses. It can also replace 15 other tests. We recommend using this test worldwide as the first choice,” said Lisenka Vissers, Professor of Translational Genomics at Radboud University.

“Thanks to long reads, we obtain an even more complete view of DNA and can detect complex and hard-to-find abnormalities. We then link these to specific conditions. In this way, our knowledge grows and we can make more diagnoses,” said Alexander Hoischen, Professor of Genomic Technologies at Radboud University.

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