Validation of genetic diagnosis of neurological and neuromuscular diseases using faster, smaller and cheaper sequencing technologies

A new DNA test, developed by researchers at the Garvan Institute of Medical Research in Sydney and collaborators from Australia, the UK and Israel, has identified a range of difficult-to-diagnose neurological and neuromuscular genetic diseases more quickly and more accurately than existing proofs.

“We correctly diagnosed all patients with previously known conditions, including Huntington’s disease, fragile X syndrome, hereditary cerebellar ataxias, myotonic dystrophies, myoclonic epilepsies, motor neuron diseases, etc.” , says Dr. Ira Deveson, head of genomic technologies at the Garvan Institute and lead author of the study.

The diseases covered by the test belong to a class of more than 50 diseases caused by unusually long repetitive DNA sequences in a person’s genes – known as “short tandem repeat expansion disorder (STR )”.

“They are often difficult to diagnose due to the complex symptoms that patients present with, the difficult nature of these repetitive sequences and the limitations of existing genetic testing methods,” says Dr Deveson.

The study, published today in Scientists progressshows that the test is accurate and allows the team to begin validations to make the test available in pathology departments around the world.

A patient who took part in the study, John, first realized something was wrong when he experienced unusual balance problems during a ski lesson.

“It was very worrying to have symptoms that over the years got worse; from being active and mobile to not being able to walk unassisted. I had test after test for over ten years and absolutely no answers as to what was wrong,” says John, who was eventually diagnosed with a rare genetic condition called CANVAS, which affects the brain.

“It was reassuring to finally have my diagnosis genetically confirmed, and it’s exciting to know that in the near future other people with these types of conditions will be able to get diagnosed faster than me,” he says. .

“For patients like John, the new test will be a game-changer, helping to end what can often be a harrowing diagnostic odyssey,” says Dr. Kishore Kumar, study co-author and clinical neurologist at the hospital. Concord.

Repeat expansion disorder can be passed down through families, can be life-threatening, and usually involves muscle and nerve damage, as well as other complications throughout the body.

Faster and more accurate diagnosis for patients avoids a “diagnostic odyssey”

Current genetic testing for expansion disorders can be hit-or-miss, says Dr. Kumar. “When patients show symptoms, it can be difficult to tell which of these more than 50 gene expansions they might have, so their doctor must decide which genes to test based on the person’s symptoms and family history. If this test comes back negative, the patient is left with no response. These tests can go on for years without finding the genes involved in their disease. It’s what we call ‘the diagnostic odyssey’, and it can be quite stressful for patients and their families,” he says.

“This new test will completely revolutionize the way we diagnose these diseases, since we can now test all disorders at once with a single DNA test and give a clear genetic diagnosis, helping patients avoid years of muscle or nerve biopsies. useless for diseases they don’t “have, or risky treatments that suppress their immune systems,” says Dr. Kumar.

Although repeat expansion disorder cannot be cured, earlier diagnosis can help doctors identify and treat complications of the disease, such as heart problems associated with Friedreich’s ataxia, earlier.

Search for known and new 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.

“We programmed the Nanopore device to fine-tune the approximately 40 genes known to be involved in these disorders and to read the long repeated DNA sequences that cause the disease,” he says. “By untangling the two strands of DNA and reading the sequences of repeated letters (combinations of A, T, G or C), we can look for abnormally long repeats in the patient’s genes, which are hallmarks of the disease. “

“In a single test, we can search for all known pathogenic repeat expansion sequences and potentially uncover new sequences that may be involved in diseases that have not yet been described,” says Dr. Deveson.

Scaling to wider use over the next five years

The Nanopore technology used in the test is smaller and cheaper than standard tests, which the team hopes will make it easier to adopt in pathology labs. “With Nanopore, the genetic sequencing device has gone from the size of a refrigerator to the size of a stapler and costs around $1,000, compared to the hundreds of thousands needed for traditional DNA sequencing technologies,” says Dr. Deveson.

The team expects its new technology to be used in diagnostic practice within two to five years. One of the key steps towards this goal is to obtain appropriate clinical accreditation for the method.

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

“Adult genetic disorders have not received as much research attention as those that appear early in life,” she says. “By finding more people with these rare adult diseases and those who may be pre-symptomatic, we will be able to learn more about a whole range of rare diseases through cohort studies that would otherwise be difficult to do. .”

The work was supported mainly by philanthropic funding from the Kinghorn Foundation.