New DNA Test May Cut Disease Diagnosis From ‘Decades to Days’

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A new DNA test has been developed to simultaneously screen for more than 50 genetic neuromuscular diseases, including Friedreich’s Ataxia (FA), helping to diagnose patients far more quickly than standard genetic testing techniques, according to a recent study.

“This new test will completely revolutionize how we diagnose these diseases, since we can now test for all the disorders at once with a single DNA test and give a clear genetic diagnosis, helping patients avoid years of unnecessary muscle or nerve biopsies for diseases they don’t have, or risky treatments that suppress their immune system,”  Kishore Kumar, MD, PhD, one of the study’s investigators, said in a press release.

The study, “Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing,” was published in Science Advances

FA is caused by mutations in the FXN gene, most commonly consisting of excessive repeats of three nucleotides (DNA building blocks) – one guanine (G) and two adenines (A) – in a region of the gene. While the sequence is repeated around five to 33 times in healthy people, FA patients sometimes have hundreds of repeats, disrupting the gene’s ability to produce its protein, frataxin.

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FA and around 50 other disorders that involve similar nucleotide repeats are called short tandem repeat (STR) expansion disorders. They can be difficult to diagnose using current genetic testing methods, which are both time-consuming and expensive.

“When patients present with symptoms, it can be difficult to tell which of these 50-plus genetic expansions they might have, so their doctor must decide which genes to test for based on the person’s symptoms and family history,” Kumar said.

“If that test comes back negative, the patient is left without answers. This testing can go on for years without finding the genes implicated in their disease. We call this the ‘diagnostic odyssey,’ and it can be quite stressful for patients and their families,” Kumar added.

The team, led by researchers at the Garvan Institute in Sydney, Australia, has developed a technique to quickly and accurately test for FA and other STR expansion diseases in parallel, using DNA collected from a person’s blood.

The investigators took advantage of nanopore DNA sequencing technology, developed by Oxford Nanopore Technologies to help sequence complex and repetitive regions in the DNA, and programmed the sequencing device to read only recognized nucleotide repeats in 37 genes known to be involved in neurological and neuromuscular diseases.

They then evaluated the technique in samples from 37 participants, 25 of whom had a diagnosed genetic neurological disease.

Two of these patients had FA and the test was able to accurately identify the disease-causing FXN expansion in both of them. The technique could also recognize mutations for other neuromuscular disorders, including Huntington’s disease, myotonic dystrophy, and fragile X syndrome.

“In the one test, we can search for every known disease-causing repeat expansion sequence, and potentially discover novel sequences likely to be involved in diseases that have not yet been described,” said Ira Deveson, PhD, the study’s lead author. 

The technique is smaller and cheaper than other technologies and it helps shorten the time it takes to identify the right diagnose from years to just days, the researchers said. This means disease complications, such as heart disease, found in FA, can be addressed much sooner.

The device can also be used to examine other genetic differences. For example, the researchers demonstrated that the technology could be programmed to identify genetic differences among 28 pharmacogenomic genes, which may predict a person’s ability to metabolize certain medications.

“While this is not the primary purpose of our targeted sequencing assay, secondary findings of this nature may better inform patient care at no extra cost, underscoring the appealing flexibility of programmable sequencing with [the Nanopore Technology],” the team wrote. 

As a research tool, it will also help scientists understand which lengths of the repeats lead to disease and which may occur in healthy people, they said. 

“We anticipate that this will be a powerful approach to STR gene discovery and provide molecular diagnoses for many previously unsolved cases in the future,” the researchers wrote.

The team hopes to see the technology used in the clinic within the next two to five years, noting that eventually it could be programmed to diagnose many genetic diseases – not just those with STR expansions.

One study participant with a rare STR expansion disease called CANVAS, recalls waiting more than 10 years for an eventual diagnosis. 

“It was reassuring to finally confirm my diagnosis genetically, and it’s exciting to know that, in the near future, others with these types of conditions will be able to get a diagnosis quicker than I did,” he said.