Single test for over 50 genetic diseases will cut diagnosis from decades to days

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• A single DNA test has been developed that can screen a patient’s genome for over 50 genetic neurological and neuromuscular diseases such as Huntington’s disease, muscular dystrophies and fragile X syndrome.
• The new test avoids a ‘diagnostic odyssey’ for patients that can take decades.
• The team, from Australia, UK and Israel, has shown, in a paper today in Science Advances that the test is accurate. They are now working on validations to make it available in pathology labs.
• They expect it to be standard in global pathology labs within five years.

A new DNA test, developed by researchers at the Garvan Institute of Medical Research in Sydney and collaborators from Australia, UK and Israel, has been shown to identify a range of hard-to-diagnose neurological and neuromuscular genetic diseases quicker and more-accurately than existing tests.

‘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,’ says Dr Ira Deveson, Head of Genomics Technologies at the Garvan Institute and senior author of the study.

The diseases covered by the test belong to a class of over 50 diseases caused by unusually-long repetitive DNA sequences in a person’s genes – known as ‘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,’ says Dr Deveson.

The study, published today in Science Advances , shows that the test is accurate, and allows the team to begin validations to make the test available in pathology services around the world.

A patient who participated in the study, John, first realised something wrong when he experienced unusual problems balancing 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,’ says John, who was eventually diagnosed with a rare genetic disease called CANVAS, which affects 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,’ he says.

‘For patients like John, the new test will be a game-changer, helping to end what can often be a taxing diagnostic odyssey,’ says Dr Kishore Kumar, a co-author of the study and neurologist at Concord Hospital and the University of Sydney, and visiting scientist at the Garvan Institute.

Repeat expansion disorders can be passed on through families, can be life threatening and generally involve muscle and nerve damage, as well as other complications throughout the body.

Quicker, more-accurate diagnosis for patients avoids ‘diagnostic odyssey’

Current genetic testing for expansion disorders can be ‘hit and miss’, says Dr Kumar. ‘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,’ he says.

‘This new test will completely revolutionise 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,’ says Dr Kumar.

Although repeat expansion disorders cannot be cured, a quicker diagnosis can help doctors identify and treat disease complications earlier, such as heart issues associated with Friedreich’s ataxia.

Scanning for known and novel 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’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,’ he says. ‘By unravelling 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.’

‘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,’ says Dr Deveson.

Upscaling to wider use in the next five years

The Nanopore technology used in the test is smaller and cheaper than standard tests, which the team hopes will smooth its uptake into pathology labs. ‘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’ says Dr Deveson.

The team expects to see their new technology used in diagnostic practice within the next two to five years. One of the key steps towards that goal is to gain appropriate clinical accreditation for the method.

Once accredited, the test will also transform research into genetic diseases, says 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.

‘Adult-onset genetic disorders haven’t received as much research attention as those that appear in early life,’ she says. ‘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.’

–ENDS–

The research was led by the Garvan Institute of Medical Research in Sydney, with UNSW Sydney, University of Sydney, Harry Perkins Institute of Medical Research, Pathwest, Westmead Hospital, Royal North Shore Hospital, University College London, Beilinson Hospital, ANZAC Research Institute, Concord Hospital.

The work was supported with funding from The Kinghorn Foundation, Medical Research Futures Fund (MRFF), NHMRC, Australian Government Research Training Program (RTP) Scholarship, Margaret and Terry Orr Memorial Fund.

Media contact:

Australia: Laura Boland, Science in Public, laura@scienceinpublic.com.au

UK: Ruth Francis, Communications Consultant, ruthfrankiefrancis@gmail.com

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Paper Details

Comprehensive genetic diagnosis of tandem repeat expansion
disorders with programmable targeted nanopore sequencing

DOI: www.science.org/doi/10.1126/sciadv.abm5386

Abstract

Over fifty neurological and neuromuscular diseases are caused by short-tandem repeat (STR) expansions, with 37 different genes implicated to date. We describe the use of programmable targeted long-read sequencing with Oxford Nanopore’s ReadUntil function for parallel genotyping of all known neuropathogenic STRs in a single assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of STR sites, from a list of pre-determined candidates. This correctly diagnoses all individuals in a small cohort (n=37) including patients with various neurogenetic diseases (n=25). Targeted long-read sequencing solves large and complex STR expansions that confound established molecular tests and short-read sequencing, and identifies non-canonical STR motif conformations and internal sequence interruptions. We observe a diversity of STR alleles of known and unknown pathogenicity, suggesting long-read sequencing will redefine the genetic landscape of repeat disorders. Finally, we show how the inclusion of pharmacogenomics genes as secondary ReadUntil targets can further inform patient care.

Authors

Igor Stevanovski¹, Sanjog R. Chintalaphani^1,2,18, Hasindu Gamaarachchi^1,3, James M. Ferguson¹, Sandy S. Pineda^4,5, Carolin K.Scriba^6,7, Michel Tchan⁸, Victor Fung⁸, Karl Ng⁹, Andrea Cortese^10,11, Henry Houlden^10,11, Carol Dobson-Stone⁵, Lauren Fitzpatrick⁵, Glenda Halliday⁵, Gianina Ravenscroft⁶, Mark R. Davis⁶, Nigel G. Laing^6,7, Avi Fellner^1,12,13, Marina Kennerson^14,15,16, Kishore R.Kumar^1,16,17, Ira W. Deveson^1,18

Organisations

1. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
2. School of Medicine, University of New South Wales, Sydney, NSW, Australia.
3. School of Computer Science and Engineering, University of New South Wales, Sydney, NSW, Australia.
4. Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
5. The University of Sydney, Brain and Mind Centre and School of Medical Sciences, Faculty of Medicine and Health, Camperdown,
   NSW, Australia.
6. Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA, Australia.
7. Diagnostic Genomics, PathWest Laboratory Medicine WA, Nedlands, WA, Australia.
8. Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, Australia.
9. Department of Neurology and Clinical Neurophysiology, Royal North Shore Hospital and The University of Sydney, Sydney, NSW,
   Australia
10. Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
11. The National Hospital for Neurology and Neurosurgery, London, UK
12. Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
13. The Neurology Department, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
14. Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, NSW, Australia.
15. Faculty of Health and Medicine, University of Sydney, Camperdown, NSW, Australia.
16. Molecular Medicine Laboratory, Concord Hospital, Concord, NSW, Australia.
17. Neurology Department, Central Clinical School, Concord Repatriation General Hospital, University of Sydney, Concord, NSW,
    Australia.
18. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia