We capture these modifications as a bonus—two in one.
For the hundreds of millions of people living with rare genetic disorders, the journey toward a diagnosis has long been one of years, uncertainty, and exhausting rounds of inconclusive tests. Researchers at Radboud University Medical Center and Maastricht UMC+ have now published evidence in the New England Journal of Medicine that a single long-read genome sequencing test can replace fifteen separate diagnostic procedures while improving diagnosis rates by three percent. By reading DNA in segments up to twenty thousand building blocks long — rather than the three hundred fragments current methods rely on — the test assembles a far more complete picture of the genome, including epigenetic modifications that standard diagnostics routinely miss. In doing so, it offers something profound to those who have waited: not just a faster answer, but the possibility of one at all.
- Four hundred million people worldwide carry a rare genetic disorder, yet most endure years of inconclusive testing before receiving — if ever — a diagnosis that could guide their treatment and life decisions.
- Current diagnostic methods read DNA in tiny, difficult-to-assemble fragments and require up to fifteen separate tests, leaving complex abnormalities and epigenetic changes invisible to clinicians.
- The new long-read sequencing test reads DNA segments sixty times longer than current methods, automatically capturing both structural variants and epigenetic modifications in a single procedure.
- A real-world trial at the Undiagnosed Hackathon in Nijmegen demonstrated the test's power in practice, with 150 specialists identifying five new diagnoses among 33 families in a single weekend.
- Researchers are now calling for global adoption of the test as the first-line diagnostic standard, with diagnostic yields expected to rise further as newly detected abnormalities are linked to specific conditions.
For families living with undiagnosed rare genetic disorders, the search for answers has long meant years of appointments, repeated testing, and dead ends. A child presents with symptoms that fit no known condition; doctors run test after test — sometimes fifteen — and still find nothing. When a diagnosis finally arrives, it changes everything: it names what is happening, connects families to others facing the same struggle, and opens the door to informed decisions about treatment and the future.
Researchers at Radboud University Medical Center and Maastricht UMC+ believe they have found a way to shorten that wait dramatically. Their new DNA test, based on long-read genome sequencing, was compared against current diagnostic methods in one thousand patients and published in the New England Journal of Medicine. It found diagnoses three percent more often — and accomplished the work of fifteen separate tests in a single procedure.
The difference lies in how the test reads genetic code. Standard diagnostics examine DNA in fragments of roughly three hundred building blocks, then attempt to reconstruct the full picture from those small pieces. The new test reads segments of up to twenty thousand building blocks at a time, producing a far clearer and more complete view of the genome. It also detects epigenetic modifications — chemical markers on the outside of DNA that can switch genes on or off — which current methods can only capture through additional specialized testing. With long-read sequencing, those modifications are captured automatically.
The scale of the problem the test addresses is immense. More than seven thousand rare genetic disorders exist, and though each affects fewer than one in two thousand people, together they touch roughly four hundred million lives worldwide. Eighty percent have a genetic origin. For most patients, the road to diagnosis is long and uncertain — and without one, families cannot access targeted treatments, connect with others in similar situations, or make informed reproductive choices.
The researchers expect diagnostic rates to keep improving. As long-read sequencing is used more widely, specialists will identify complex abnormalities that current methods miss and gradually link them to specific conditions, expanding the knowledge base with each discovery. That process was already visible at the Undiagnosed Hackathon in Nijmegen, where nearly one hundred fifty specialists from Dutch university medical centers gathered to work on thirty-three undiagnosed families — and identified five new diagnoses over a single weekend. The team is now urging the global medical community to adopt the test as the standard first step in diagnosing rare genetic disorders.
For years, the families of people with rare genetic disorders have lived in a kind of limbo. A child shows symptoms that don't fit neatly into any known condition. Doctors run test after test—sometimes fifteen separate ones—and still come away empty-handed. The diagnosis, when it finally arrives, can take years. But that diagnosis, once it comes, changes everything: it explains what's happening, it opens doors to others living with the same condition, it lets families make informed choices about their futures.
Now researchers at Radboud University Medical Center and Maastricht UMC+ say they have found a way to make that process faster and more reliable. They've developed a new DNA test based on long-read genome sequencing, and they're urging the medical world to adopt it as the standard first step in diagnosing rare genetic disorders. The evidence is in a study they published in the New England Journal of Medicine: when they compared their new test to the current diagnostic approach in one thousand patients, the new test found diagnoses three percent more often. It also did the work of fifteen separate tests in a single procedure.
The scale of the problem is staggering. A rare disease, by definition, affects fewer than one in two thousand people. Yet because there are more than seven thousand different rare genetic disorders, roughly four hundred million people worldwide are living with one. Eighty percent of these conditions have a genetic root. For most of them, getting a diagnosis is a years-long odyssey of appointments and tests and dead ends. The toll is real: without a diagnosis, families live with uncertainty, they can't access targeted treatments, they can't connect with others facing the same struggle, and they can't make informed decisions about having children.
The innovation lies in how the test reads DNA. Current diagnostics examine a person's genetic code in fragments of about three hundred building blocks, then piece those fragments together like a jigsaw puzzle made of tiny, difficult pieces. The new test reads segments of up to twenty thousand building blocks at a time—vastly larger chunks that make the puzzle far easier to assemble. The result is a more complete and accurate picture of the genome. But there's another layer to it. The test doesn't just read the DNA sequence itself; it also detects modifications on the outside of the DNA, chemical markers that can switch genes on or off and sometimes cause disease. These epigenetic changes are crucial to understanding certain disorders, but detecting them with current methods requires additional specialized tests. The long-read approach captures them automatically.
Christian Gilissen, a professor of genome bioinformatics involved in the research, describes it plainly: "With current diagnostics, this requires additional specialized tests, but with long reads we capture these modifications as a bonus—two in one." Lisenka Vissers, the translational genomics professor leading the effort, is direct about what comes next: "We showed that the new test yields three percent more diagnoses. It can also replace fifteen other tests. We recommend using this test worldwide as the first choice."
The researchers expect the diagnostic yield to keep climbing. Alexander Hoischer, a professor of genomic technologies, explains that as they use long-read sequencing more widely, they'll detect complex abnormalities that current methods miss, then link those abnormalities to specific conditions. Each new connection expands the knowledge base and makes future diagnoses possible. That process played out in real time at a recent event called the Undiagnosed Hackathon in Nijmegen, where nearly one hundred fifty specialists from Dutch university medical centers gathered to work on thirty-three families with undiagnosed genetic conditions. Using the long-read test and pooling their expertise, they identified five new diagnoses in a single weekend.
What's at stake is the difference between living in the dark and living with answers. For the millions of people worldwide still waiting for a diagnosis, the adoption of this test could mean the end of that wait.
Citações Notáveis
We showed that the new test yields three percent more diagnoses. It can also replace fifteen other tests. We recommend using this test worldwide as the first choice.— Lisenka Vissers, Professor of Translational Genomics, Radboud University Medical Center
Thanks to long reads, we obtain an even more complete view of DNA and can detect complex and hard-to-find abnormalities. In this way, our knowledge grows and we can make more diagnoses.— Alexander Hoischer, Professor of Genomic Technologies
A Conversa do Hearth Outra perspectiva sobre a história
Why does it matter that the test reads longer segments of DNA—twenty thousand building blocks instead of three hundred?
Imagine trying to assemble a photograph from tiny puzzle pieces versus larger ones. With tiny pieces, you can't see the pattern until you've placed hundreds of them. With larger pieces, the picture emerges much faster and more clearly. The same is true for DNA. Longer reads let you see structural variations and complex abnormalities that get lost when you're working with fragments.
And the three percent improvement in diagnosis rates—is that significant?
It sounds small until you remember we're talking about four hundred million people with rare genetic disorders. Three percent of that is millions of people who might finally get answers. But more importantly, it's not just the percentage—it's that one test replaces fifteen. That's a massive shift in how efficiently we can work.
Why has diagnosis taken so long historically?
Because rare diseases are, by definition, rare. Doctors see them infrequently, so they don't think of them first. And because the genetic causes are often complex—structural variations, epigenetic changes—the old fragmented approach to reading DNA simply couldn't detect them reliably.
What changes when someone finally gets a diagnosis?
Everything. They stop wondering if they're imagining their symptoms. They can find communities of others with the same condition. They can access treatments designed for their specific disorder. And if they want to have children, they can make informed decisions about genetic risk. The diagnosis itself is often less important than the clarity it brings.
Do you think hospitals will actually adopt this as standard?
The researchers are publishing in the New England Journal of Medicine and making a clear case. But adoption depends on cost, training, and whether health systems are willing to change established workflows. That's the real test now.