Researchers in the Netherlands have developed a DNA test for rare diseases that can provide much more comprehensive results than standard diagnostics in a shorter amount of time. A study published today in the New England Journal of Medicine reports that this new approach could replace 15 other genetic tests with a single analysis while increasing the number of patients who successfully receive a diagnosis.
Taken together, all rare diseases affect approximately 400 million people worldwide. Of the more than 7,000 rare diseases that have been identified so far, about 80% are caused by genetic mutations. Obtaining a diagnosis can be critical for people suspected of having a rare disease, offering them perspective for the future, better guidance and treatment, and less uncertainty. However, these patients often have to undergo multiple rounds of testing and wait years before receiving a definitive answer.
The new test is based on long-read genome sequencing, a technology that can read significantly longer stretches of DNA before assembling them into a complete genome. While conventional genomic tests typically read fragments around 300 nucleotides long, long-read sequencing can analyze stretches of up to 20,000 nucleotides at a time. The longer reads make it easier to accurately assemble the full genome, providing a more complete picture of the patient’s genetic makeup.
“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,” says Alexander Hoischen, PhD, professor of genomic technologies at Radboud University Medical Center. “In this way, our knowledge grows and we can make more diagnoses.”
In addition, the test can detect epigenetic modifications in the genome that affect gene function without altering the underlying DNA sequence. Although these modifications can be responsible for some rare disorders, conventional testing methods are currently unable to detect them.
“With current diagnostics, this requires additional specialized tests, but with long reads we capture these modifications as a bonus—two in one,” explains Christian Gilissen, PhD, professor of genome bioinformatics at Radboud University Medical Center.
Earlier this year, the technology was used as part of the National Undiagnosed Hackathon, where over 140 experts across the Netherlands came together to search for a diagnosis for 33 families. Long-read sequencing was used to map their DNA in detail, leading to five new confirmed diagnoses within two days as well as strong suspicion of a diagnosis for another eight families.
As the number of rare disease diagnoses continues to rise, this new test could make the diagnostic process much faster and more efficient. Long-read sequencing could also help researchers identify and investigate the genetic drivers of rare conditions, many of which remain largely understudied.
Based on these findings, Lisenka Vissers, PhD, professor of translational genomics at Radboud University Medical Center, calls for the technology to be adopted worldwide as the first choice diagnostic approach when testing patients suspected to have a rare genetic disorder.
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