New test identifies the genetic cause of inherited muscle disease

A world-first test developed by researchers at the Garvan Institute of Medical Research has identified the genetic cause of inherited muscle disease in people who remained without answers after years, sometimes decades, of standard testing.

Published in Nature Communications, the study applied the test to 53 Australians with known or suspected inherited muscle disease, including 31 whose previous genetic testing had failed to identify a cause. Over a third of those unsolved cases received a diagnosis through the new test. On average, these participants had been living without answers to their symptoms for 14 years.

Inherited muscle diseases, which include muscular dystrophies, affect an estimated 6,000 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.

The new test uses long-read 'nanopore' sequencing, a newer technology that 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. 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."

Dr. Ira Deveson, Lab Head at Garvan and co-senior author

Why so many people go undiagnosed

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, 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 – a gap that long-read sequencing closes.

New genetic causes of muscle disease also continue to be identified, and each one takes time to build into an accredited clinical test – which means many people affected by conditions recognised in the last five to 10 years cannot be diagnosed. The new test covers them all, while at the same time detecting variants that have been known about for a longer time.

What a diagnosis makes possible

For some participants, the new test identified a gene variant that no Australian clinical test currently looks for. For others, it corrected a misdiagnosis.

Either way, the results have significant practical consequences, says Associate Professor Kishore Kumar, Group Leader at Garvan, neurologist at Concord Repatriation General Hospital and co-senior author. "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. This new test puts Australia at the cutting edge of genetic diagnosis, and other countries will follow."

Dr Dennis Yeow, neurologist and PhD candidate at The University of Sydney who co-led the study, says the impact on individuals is often striking. "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. Being able to finally give them a name for what they have is significant, both for them and for their families."

Toward routine clinical use

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.

Dr Andre Reis, Senior Research Officer at Garvan and lead bioinformatician on the study built much of the analysis framework that makes the test workable in a clinical context. "Long-read sequencing generates a huge amount of complex information about a person's DNA. 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," he says.

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," Dr. Deveson says. "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."