Researchers have developed a technique that can identify errors caused by mutations linked to a range of genetic disorders, including forms of muscular dystrophy, Huntington’s disease and amyotrophic lateral sclerosis (ALS), which could accelerate accurate diagnosis of these conditions.

The technique, developed by researchers led by the University of Cambridge, uses RNA samples stretched into usable shapes and tiny glass holes known as nanopores, to analyse sections of RNA that have multiplied far beyond their normal length.

These expanded stretches interrupt the cell’s machinery and can trigger conditions known as repeat expansion disorders, which affect approximately one in every 280 people. Scientists say that as many of 90% of people with these disorders are undiagnosed, which poses the need for a fast and affordable test for sizing the repeats.

The genomic DNA in our cells contains many stretches of simple repetitive sequences, but in repeat expansion disorders, the size of the expansion will often affect the onset and severity of the disease. However, measuring these expansions is notoriously difficult.

“RNA is incredibly informative in terms of what it can tell you about the disorders we want to study, but it’s also incredibly fragile and often challenging to study,” said lead author Gerardo Patiño‑Guillén, from Cambridge’s Cavendish Laboratory. “Current techniques were designed for DNA, so they often lose the information in RNA that signals disease. We wanted to fix that.”

Measuring tandem repeat expansions usually relies on polymerase chain reaction (PCR), which many people will recall from the COVID-19 pandemic. However, PCR can distort the true length of the repeated section, while newer sequencing methods frequently encounter errors in the repeated sections.

Accurately sizing repeat expansions is important for diagnosis, because symptoms often depend on how large the repeat region has become. For example, people with around 50 repeats in the DMPK gene – the threshold for myotonic dystrophy type 1, the most common muscular dystrophy in adults – may only have mild symptoms. But any further increase in repeated sections can significantly raise the risk of a more severe form of the disease, which could be passed down to children.

In congenital central hypoventilation syndrome, another repeat expansion disorder, a difference of only six repeats can determine whether a newborn baby has normal breathing control or experiences dangerous respiratory failure during sleep.

Working with colleagues from the University of Belgrade in Serbia, the Cambridge researchers stretched RNA molecules into labelled nanostructures using short pieces of DNA, then passed the structures through a nanopore. As the molecules travelled through the pore, they produced an electrical signal whose pattern corresponded to the RNA’s shape, including how many repeats it contained.

This RNA origami method achieved a resolution of just 18 nucleotides — the essential building blocks of RNA and DNA— enough to tell apart healthy and disease‑associated repeat sections. The results are reported in the journal Nature Communications.

Patiño‑Guillén says the ability to detect such subtle differences with minimal RNA is particularly important given the tiny amounts of patient material often available in clinical settings. “One of the reasons our collaborators in Serbia were interested is that we only need extremely small amounts of RNA to get a good result,” he said.

While the team have achieved promising results, in the lab, they are hoping to improve their technology to the point where it can be scaled to a commercial platform. The team has not yet tested patient samples, and the platform must be scaled up so that many nanopores operate in parallel — a prerequisite for producing results fast enough for routine diagnostics.

The University spin‑out company Cambridge Nucleomics, co‑founded by senior author Professor Ulrich Keyser, also from the Cavendish Laboratory, is developing the method into a diagnostics platform.

While the technique is unlikely to immediately replace routine PCR-based diagnostic tests, it could complement sequencing technology by providing fast, targeted tests capable of sizing the expansion for families known to carry repeat‑expansion disorders, or for clinicians needing quick answers.

In the longer term, Patiño‑Guillén sees potential for monitoring the response to disease-modifying therapies that are expected to be approved for repeat expansion disorders in the coming years.

“We have a very strong molecular platform,” he said. “We’re confident about what it can do in controlled samples. The next challenge is proving it works just as well in clinical material.”

The research was supported in part by the European Research Council, the European Union, and the Engineering and Physical Sciences Research Council (EPSRC), part of UK Research and Innovation (UKRI). Gerardo Patiño-Guillén is a Member of Churchill College, Cambridge.

Reference:
Gerardo Patino Guillen et al. ‘Quantification of disease-associated RNA tandem repeats by nanopore sensing.’ Nature Communications (2026) DOI: 10.1038/s41467-026-72819-5