DNA test finds genetic cause of inherited muscle disease

A DNA test developed by researchers at the Garvan Institute of Medical Research has identified the genetic cause of inherited muscle disease in people who have remained without answers after years of standard testing, as revealed in a study published in the journal Nature Communications.

Inherited muscle diseases, which include muscular dystrophies, affect an estimated 6000 Australians. They gradually weaken and waste the muscles, often robbing people of the ability to walk, swallow, speak clearly or use their hands. They can begin in childhood or adulthood, worsen over time, and there are currently no cures.

Standard diagnostic tests for inherited muscle disease look for one kind of DNA change at a time — but these conditions can be caused by many genetic changes. Some involve single-letter errors in the DNA code, while others involve large missing or duplicated sections, unstable expansions of repeated sequences, or epigenetic chemical marks that switch genes on and off. Until now, no single test could detect all of these changes at once; furthermore, new genetic causes of muscle disease continue to be identified, and each one takes time to build into its own accredited clinical test.

What makes the new test special is its use of Oxford Nanopore Technologies’ long-read sequencing, which reads much longer stretches of DNA than standard methods and can pick up complex genetic changes that older tests routinely miss. In a single experiment, it screens more than 300 genes known to cause inherited muscle disease and detects the full range of DNA changes behind them.

“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 Garvan and co-senior author on the study. “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.”

The study outlined the application of the test to 53 Australians with known or suspected inherited muscle disease, including 31 whose previous genetic testing had failed to find a cause. Over a third of those unsolved cases received a diagnosis, with the test identifying in some participants a gene variant that no Australian clinical test currently looks for. For other participants, it corrected a misdiagnosis. Either way, the results have significant practical consequences.

“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,” said neurologist Dr Dennis Yeow, a PhD candidate at The University of Sydney who co-led the study. “Being able to finally give them a name for what they have is significant, both for them and for their families.”

“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,” added Associate Professor Kishore Kumar, Group Leader at Garvan and co-senior author on the study. “Without it, many of those doors stay closed.”

The team is now working with NSW Health Pathology’s Molecular Medicine Laboratory at Concord Hospital to bring the test into routine care. The researchers estimate it could be available across Australia within about two years.

“Long-read sequencing generates a huge amount of complex information about a person’s DNA,” noted Dr Andre Reis, Senior Research Officer at Garvan and lead bioinformatician on the study. “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.”

While the study focused on muscle disease, the same test approach could be applied to other rare inherited conditions.

“The long-read technology we have applied in this test is disease-agnostic,” Deveson said. “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.”

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