UCL Queen Square Institute of Neurology


Single test for over 50 genetic diseases will cut diagnosis from decades to days

8 March 2022

A new DNA test, developed with the help of UCL Queen Square Institute of Neurology scientists, has been shown to identify a range of hard-to-diagnose neurological and neuromuscular genetic diseases quicker and more accurately than existing tests.


In the study, published in Science Advances, the genomic sequencing technology was able to correctly diagnose all patients with conditions that were already known, including Huntington’s disease, fragile X syndrome, hereditary cerebellar ataxias, myotonic dystrophies, myoclonic epilepsies, and motor neuron disease

The diseases covered by the test belong to a class of over 50 diseases caused by unusually long repetitive DNA sequences in a person’s genes – known as ‘Short Tandem Repeat (STR) expansion disorders’.

Developed at the Garvan Institute of Medical Research in Sydney, with Australian collaborators, along with scientists at UCL and teams in Israel, the researchers are now designing validations – a framework ensuring laboratory test data and results are consistent, accurate and precise. The team hopes the test will be ‘standard’ in global pathology labs within five years.

Commenting on the study, co-authors, Professor Henry Houlden and Dr Andrea Cortese (UCL Queen Square Institute of Neurology) said: "Repeat expansions are a leading cause of neuromuscular and neurodegenerative disease. However, their genetic testing is often challenging and time consuming.
“The new method described represents a significant step forward in field of repeat expansion diseases and will hopefully enable to reach an early and accurate diagnosis in patients affected by this disabling group of conditions.”

Repeat expansion disorders can be passed on through families, can be life threatening and generally involve muscle and nerve damage, as well as other complications throughout the body.

Dr Ira Deveson, Head of Genomics Technologies at the Garvan Institute and senior author of the study, said: "They are often difficult to diagnose due to the complex symptoms that patients present with, the challenging nature of these repetitive sequences, and limitations of existing genetic testing methods.”

Quicker, more-accurate diagnosis for patients avoids ‘diagnostic odyssey’

Current genetic testing for expansion disorders can be “hit and miss”, says Dr Kishore Kumar, a co-author of the study and neurologist at Concord Hospital and the University of Sydney, and Visiting Scientist at the Garvan Institute.

“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. 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,” he says.
“This new test will completely revolutionise 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,” Dr Kumar added.

Although repeat expansion disorders cannot be cured, a quicker diagnosis can help doctors identify and treat disease complications earlier, such as heart issues associated with Friedreich's ataxia.

Scanning for known and novel diseases

Using a single DNA sample, usually extracted from blood, the test works by scanning a patient’s genome using a technology called Nanopore sequencing.

Dr Deveson said: ”We’ve programmed the Nanopore device to hone in on the roughly 40 genes known to be involved in these disorders and to read through the long, repeated DNA sequences that cause disease. By unravelling the two strands of DNA and reading the repeated letter sequences (combinations of A, T, G or C), we can scan for abnormally long repeats within the patient’s genes, which are the hallmarks of disease.
“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.”

Impact on patients

A patient who participated in the study, John, first realised something was wrong when he experienced unusual problems balancing during a ski lesson.

"It was very worrying having symptoms that, over the years, increased in severity; from being active and mobile to not being able to walk without support. I had test after test for over 10 years and absolutely no answers as to what was wrong," said John, who was eventually diagnosed with a rare genetic disease called CANVAS, which affects the brain.
"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."
"For patients like John, the new test will be a game-changer, helping to end what can often be a taxing diagnostic odyssey," Dr Kumar said.

Upscaling to wider use in the next five years

The Nanopore technology used in the test is smaller and cheaper than standard tests, which the team hopes will smooth its uptake into pathology labs.

"With Nanopore, the gene sequencing device has been reduced from the size of a fridge to the size of a stapler, and costs around $1,000, compared with hundreds of thousands needed for mainstream DNA sequencing technologies," Dr Deveson said.

The team expects to see their new technology used in diagnostic practice within the next two to five years. One of the key steps towards that goal is to gain appropriate clinical accreditation for the method.

Once accredited, the test will also transform research into genetic diseases, says Dr Gina Ravenscroft, a co-author of the study and a researcher working on rare disease genetics at the Harry Perkins Institute of Medical Research

"Adult-onset genetic disorders haven’t received as much research attention as those that appear in early life. By finding more people with these rare adult-onset diseases, and those who may be pre-symptomatic, we’ll be able to learn more about a whole range of rare diseases through cohort studies, which would otherwise be hard to do."

The research was led by the Garvan Institute of Medical Research in Sydney, with UNSW Sydney, University of Sydney, Harry Perkins Institute of Medical Research, Pathwest, Westmead Hospital, Royal North Shore Hospital, ANZAC Research Institute, Concord Hospital, (all Australia), UCL and the Beilinson Hospital, Israel.



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