A new method for decoding DNA has also proven reliable in mapping modifications on the outside of the DNA. These chemical changes regulate whether genes are switched on or off, which can influence conditions like developmental disorders. Comparing these modifications between patients leads to more accurate diagnoses. Radboudumc has been using this method since November as the first hospital worldwide on a large scale and as the first choice in the clinic.
A mutation in DNA can cause a developmental disorder. That’s why doctors search for abnormalities in the DNA code. But the code itself isn’t the whole story—modifications on the outside of the DNA also provide valuable information. For instance, DNA can be methylated, meaning certain chemical groups attached to it prevent the DNA from being transcribed. A genetic mutation can not only lead to a developmental disorder, but also to changes in this methylation.
When there is uncertainty about a diagnosis based solely on the DNA code, doctors already regularly analyze these modifications. However, the current process is cumbersome: DNA sequencing is performed in many hospitals, but analyzing methylation levels requires a separate test conducted only in specialized centers.
Specific profiles
Now, research shows that the most advanced DNA decoding technique, can also very reliably and effectively map DNA methylation at no extra cost. Two analyses in one, saving both time and money. Moreover, the additional information about DNA methylation can sometimes lead to a more precise diagnosis.
Radboudumc is the first hospital worldwide to apply this technique, so‑called long‑read sequencing, on a large scale and as a first‑choice test in the clinic. Earlier research had already shown that this method provides a more complete picture of the building blocks of DNA, and now it appears that methylation is also reliably visualized. Professor of Genome Bioinformatics Christian Gilissen of Radboudumc led this study, which has been published in Genome Medicine.
Striking variant
'With this technique, we primarily look for changes in DNA that cause genetic diseases', says Gilissen. 'But we can also detect subtle differences across the entire genome—regions that are more or less methylated. This results in specific profiles associated with certain conditions, which we call episignatures. With these profiles, you can recognize, purely from the methylation profile, that a DNA change must be present in a specific gene.'
But if a DNA mutation is the underlying cause, why would we still want to see the profile of modifications on the DNA surface? Gilissen explains: 'Sometimes we find a striking DNA change in a gene, but we’re not sure whether it causes the developmental disorder. In such cases, we can compare the methylation profile with those of other patients known to have the disorder. This helps us determine whether the mutation is truly the cause or not.' This leads to more accurate diagnoses.
About the publication
This research has been published in Genome Medicine: Genome-wide methylation detection and episignature analysis using PacBio long-read sequencing. V. Ivashchenko, M. Groot, R. Derks, A. den Ouden, G. Khazeeva, S. Heuvel, R. Timmermans, J.C. Galbany, R. Pfundt, T. Hofste, H. Yntema, L. Vissers, A. Hoischen, J. Hampstead, C. Gilissen. DOI: 10.1186/s13073-025-01506-9.
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Annemarie Eek
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