Novel DNA test helps diagnose neurological and neuromuscular genetic diseases

The Garvan Institute of Medical Research in Sydney, along with collaborators from Australia, the UK, and Israel, came up with a new DNA test that helps determine a range of hard-to-diagnose neurological and neuromuscular genetic diseases faster and more precisely compared to present tests.

Dr Kishore Kumar and Dr Ira Deveson. Image Credit: Garvan Institute of Medical Research.

We correctly diagnosed all patients with conditions that were already known, including Huntington’s disease, fragile X syndrome, hereditary cerebellar ataxias, myotonic dystrophies, myoclonic epilepsies, motor neuron disease, and more.”

Dr Ira Deveson, Study Senior Author and Head, Genomics Technologies, Garvan Institute of Medical Research

The diseases that have been covered by the test belong to a class of more than 50 diseases caused by exceptionally long repetitive DNA sequences in a person’s genes—called “Short Tandem Repeat (STR) expansion disorders.”

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.”

Dr Ira Deveson, Study Senior Author and Head, Genomics Technologies, Garvan Institute of Medical Research

The study demonstrates that the test performed is precise and enables the researchers to start validations to make the test available in pathology services throughout the world.

The study was reported in the journal Science Advances.

A patient named John, who took part in the study, initially realized that something is wrong when he experienced a strange balance 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 ten years and absolutely no answers as to what was wrong,” stated John, who was ultimately diagnosed with a rare genetic disease known as CANVAS, which tends to affect 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,” stated John

For patients like John, the new test will be a game-changer, helping to end what can often be a taxing diagnostic odyssey.”

Dr Kishore Kumar, Study Co-Author and Neurologist, Concord Hospital

Dr Kumar is also a Neurologist at the University of Sydney and a Visiting Scientist at Garvan.

Repeat expansion conditions could be passed on through families, which can be life-threatening and normally involve muscle and nerve damage, in addition to other complications throughout the body.

Quicker, more-accurate diagnosis for patients avoids “diagnostic odyssey”

The present genetic testing for expansion disorders could be “hit and miss,” said Dr Kumar.

He further stated, “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,” added Dr Kumar.

“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,” stated Dr Kumar.

Even though there is no way to cure repeat expansion disorders, a rapid diagnosis could help doctors determine and treat disease complexities earlier, like heart problems linked to Friedreich’s ataxia.

Scanning for known and novel diseases

With the help of a single DNA sample, which is generally taken from blood, the test functions by scanning a patient’s genome using a technology known as Nanopore sequencing.

Dr Kumar stated, “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 unraveling 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,” Dr Kumar adds.

“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,” stated Dr Deveson

Upscaling to wider use in the next five years

The Nanopore technology utilized in the test seems to be smaller and less expensive compared to standard tests, which the team believes will make its uptake seamless into pathology laboratories.

Deveson stated, “With Nanopore, the gene sequencing device has been reduced from the size of a fridge to the size of a stapler, and costs around $1000, compared with hundreds of thousands needed for mainstream DNA sequencing technologies.”

The researchers hope to see their novel technology being utilized in diagnostic practice in the next two to five years. One of the vital steps towards that aim is to acquire proper clinical accreditation for the technique.

As soon as it has been accredited, the test will also alter research into genetic diseases, states 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.

Dr Gina Ravenscroft added, “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.”