Single DNA assay may avoid ‘diagnostic odyssey’ for neurological and neuromuscular diseases


By Mardi Chapman

7 Mar 2022

A single DNA test has been developed that can screen a patient’s genome for over 50 genetic neurological and neuromuscular diseases caused by short tandem repeat (STR) expansions.

STR expansions in more than 40 genes have been shown to cause heritable disorders, including Huntington’s disease (HD; HTT), fragile X syndrome (FXS; FMR1), hereditary cerebellar ataxias (RFC1, FXN, and others), myotonic dystrophies (DMPK and CNBP), myoclonic epilepsies (CSTB, SAMD12, STARD7, and others), and C9orf72-related frontotemporal dementia and amyotrophic lateral sclerosis (ALS).

While unlikely to be available in routine pathology labs for about five years, the revolutionary new test avoids a ‘diagnostic odyssey’ for patients that can take decades.

“Unlike existing single-gene molecular techniques, our approach enabled unbiased sizing and sequence determination of all known neuropathogenic STR sites in a single targeted assay,” the study published in Science Advances said.

“Our multigene assay has the additional benefit of informing consenting patients of carrier status for pathogenic expansions not associated with their primary diagnosis (e.g., RFC1 AAGGG pathogenic expansion in the DM1 patient NA23265).”

The research team, from Australia, UK and Israel, has shown that the test is accurate.

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

He said STR expansion disorders were 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 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, said current genetic testing for expansion disorders can be ‘hit and miss’.

“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.”

“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,” he said.

The study said targeted STR sequencing will also be useful as a research tool.

“Much remains to be learned about the basic biology of STR expansion disorders and the distinction between a benign and pathogenic allele, particularly for recently described STR disease genes like RFC1, GIPC1, LRP12, NOTCH2NLC, and VWA1,” it said.

The researchers observed several previously unknown STR alleles in genes such as STARD7 and BEAN1, “the physiological relevance of which is currently unknown.”

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