Australian researchers have developed a new, once-off DNA test that can identify the genetic cause of inherited muscle disease.
Confirming a diagnosis of inherited muscle disease is now far easier, thanks to a first-of-its-kind development from researchers at the Garvan Institute for Medical Research.
“Many muscle diseases have no available genetic test and for others there is a separate test for each different gene involved,” said Dr Ira Deveson, lab head at the Garvan Institute and co-senior author on the new research.
“Here we’ve shown that it’s possible to test all genes at once and that’s a game-changer for someone who has been through years of inconclusive tests.”
Inherited muscle diseases, a large group of disorders including muscular dystrophies, affect as many as 6000 Australians.
These disorders are characterised by the weaking and wasting of muscles over time, stripping people of their ability to walk, swallow, and use their hands. Muscular dystrophies can begin in childhood or adulthood and there are currently no available cures.
The new approach utilises long-read ‘nanopore’ sequencing, a more modern technology that can read far longer chunks of DNA than existing methods and can identify complex genetic changes that are missed by older tests.
A single run of the novel test can screen over 300 genes associated with inherited muscle disease and identify the complete suite of DNA changes that underlie them.
The researchers’ findings were published in Nature Communications.
“Long-read sequencing generates a huge amount of complex information about a person’s DNA,” said Dr Andre Reis (PhD), a senior research officer and bioinformatician at the Garvan Institute who built most of the analysis framework that allows the test to operate in a clinical environment.
“We’ve turned that into clear, reliable findings that a diagnostic laboratory can act on. That is what takes it from a research technique to something that can genuinely help people.”
Researchers recruited 22 individuals with a confirmed genetic myopathy diagnosis and a further 31 individuals with suspected but unconfirmed genetic myopathy. The 31 people without a diagnosis had a mean disease duration of 15.5 years.
The new test replicated the diagnosis for 21 of the 22 individuals with a known myopathy but also revealed that the 22nd individual had been incorrectly diagnosed and did not have a genetic myopathy.
“Subsequent review of the clinical phenotype also revealed the presence of clinical features atypical for [facioscapulohumeral muscular dystrophy] (symmetric weakness, presence of brisk reflexes), further supporting the inaccuracy of the previous FSHD diagnosis,” the researchers noted.
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In addition, the new test provided a diagnosis for 11 of the 31 people with a suspected by unconfirmed diagnosis, seven of which were oculopharyngodistal myopathy.
“Our results demonstrate that OPDM may be a major contributor to currently undiagnosed genetic myopathies,” wrote the researchers.
“[And] in addition to OPDM and FSHD, our LRS assay led to three new genetic diagnoses involving standard small variants that were missed or incompletely characterised during previous testing.”
Lead author Dr Dennis Yeow, a neurologist from Concord Repatriation General Hospital in Sydney, said the findings had a significant impact on the individuals who participated in the study.
“Some patients had been searching for an explanation for their symptoms for over a decade, undergoing repeated investigations, including blood tests, MRI scans, neurophysiologic studies, and even muscle biopsies,” he told media.
“Being able to finally give them a name for what they have is significant, both for them and for their families.”
Professor Kishore Kumar, also a neurologist at Concord Hospital and group leader at the Garvan Institute, elaborated on the benefits of being able put a name to such disorders.
“A confirmed genetic diagnosis changes the counselling we can offer families, opens access to supports such as the National Disability Insurance Scheme, prompts monitoring for complications such as heart problems, and allows people to enrol in clinical trials that require a known genetic cause. Without it, many of those doors stay closed,” the study’s co-senior author said.
The researchers are collaborating with the Molecular Medicine Laboratory at Concord Hospital (part of NSW Health Pathology) to make the new test a part of routine care, with the team estimating it could be available to patients across the country within the next two years.
Dr Deveson said that the long-read technology developed through the study was “disease agnostic”, meaning the new approach could feasibly be used to detect other rare inherited conditions.
“What we have shown for muscle disease could, in time, be built for many of the rare genetic conditions where people currently spend years searching for a name for what they have. That is where we want this to go,” she said.
