Whole genome sequencing could help diagnose expansion repeat neurological disorders

Whole genome sequencing (WGS) has proven a reliable diagnostic technique for 13 inherited neurological disorders, paving the way for more rapid diagnoses via the NHS.

In the study, UK researchers compared the diagnostic sensitivity of WGS versus traditional methods (eg, PCR) across several 'repeat expansion' disorders. Using an initial cohort of 404 patients, the reliability of automated WGS was equivalent to standard tools, demonstrating 97.3 percent accuracy in detecting variants linked with disease. Thus, incorporation of WGS into the clinical pipeline will drastically improve the diagnostic timeline for these conditions, which often have symptomatic overlap and currently require multiple genetic tests.

'Repeat expansion disorders are estimated to affect one in 3000 people. Our study validates the use of whole genome sequencing, a newly introduced genetic test in the National Health Service, to diagnose the commonest form of inherited neurological diseases.' said Dr Ariana Tucci, clinician scientist fellow at Queen Mary University of London and University College London. These conditions, such as Huntington's disease and amyotrophic lateral sclerosis, are caused by the presence of expanded, repetitive segments of DNA in certain genes and can be arduous to diagnose due to their relative rarity or a lack of family medical history.

Application of the WGS method to 11,631 participants recruited in the 100,000 Genome Project led to 68 novel diagnoses, including an 18-year-old girl with dementia who had a repeat expansion in the ATN1 gene. However, it is important to note that caveats were observed for the FMR1 gene, associated with Fragile X syndrome. Of the 124 repeat expansions detected, 97 were manually confirmed as false positives, indicating the methodology will need refinement for certain genes before relying on an automated system.

Nonetheless, the paper signifies a major UK-wide collaboration which provides hope for undiagnosed individuals with repeat expansion disorders. This possibility is conveyed by Eileen, a patient at the Ataxia Centre in London who was diagnosed with Friedreich's ataxia during the study: 'Before my diagnosis, I thought it would be better if I had cancer as there's usually a clear path of action to help you fight the disease. Having a diagnosis isn't a cure, but at last I knew what was happening and to understand what I needed to do to delay the inevitable for as long as possible.'

The integration of WGS, which can also diagnose other genetic conditions see BioNews 1121, into the diagnostic framework of the NHS will hopefully lead to similar individuals receiving support or treatment as early as possible.

The paper was published in The Lancet Neurology.