HMN 2026: How Long-read DNA test lifts rare disease diagnoses and could replace 15 other tests

A new test provides a much more complete picture of DNA than current standard diagnostics and leads to a diagnosis more often. The test can replace 15 other tests, making it faster and more efficient. Researchers from Radboud university medical center recommend in the New England Journal of Medicine that this test be adopted everywhere as the first choice for rare genetic disorders.

A condition is considered rare if it affects fewer than 1 in 2,000 people. Nevertheless, up to 400 million people worldwide have a rare disease, as there are more than 7,000 different types. Eighty percent of these have a genetic cause. A diagnosis often takes years to obtain. Yet a diagnosis is important: It provides clarity, insight into the future, contact with others in similar situations, and the possibility to assess risks when planning to have children.

Researchers from Radboudumc and Maastricht UMC+ are working together to increase the chances of diagnosing genetic disorders. They compared current standard diagnostics—often involving multiple tests to reach a diagnosis—with a new DNA test in 1,000 patients.

“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,” says Professor of Translational Genomics Lisenka Vissers.

Jigsaw puzzle

The new test is based on so-called long-read genome sequencing. When searching for a genetic abnormality, doctors examine a person’s complete DNA. Currently, this is done in fragments of about 300 building blocks, which are then pieced together into the full DNA sequence. The new test reads segments of up to 20,000 building blocks. Like a jigsaw puzzle, assembling the DNA puzzle is much easier with such large pieces, resulting in a more complete picture.

In addition, the new test reads not only the building blocks but also modifications on the outside of the DNA. These modifications can switch genes on or off and are sometimes the cause of a rare disorder.

“Therefore, it’s important that we measure those as well,” explains Professor of Genome Bioinformatics Christian Gilissen. “With current diagnostics, this requires additional specialized tests, but with long reads we capture these modifications as a bonus—2 in 1.”

New diagnoses

The number of diagnoses is expected to keep rising in the future, says Professor of Genomic Technologies Alexander Hoischen. He and his team have previously linked genetic abnormalities to various disorders.

“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.”

Long-read sequencing was also used at the recent Undiagnosed Hackathon in Nijmegen, organized by UMCNL. Nearly 150 specialists from all Dutch university medical centers came together to search for diagnoses for 33 families. The new test mapped the DNA of all families in detail. Combined with the expertise of so many specialists, this resulted in five new diagnoses.

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