Research Supports Use of Genome Sequencing to Diagnose Repeat Expansion Disorder

Man and DNA
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Research carried out by the Genomics England Research Consortium supports the implementation of whole genome sequencing (WGS) for diagnosing neurological repeat expansion disorders.

The study, which was published in The Lancet Neurology, showed that WGS was highly accurate at detecting repeat expansions compared with standard tests and even picked up a number of cases that were not previously diagnosed.

Following the completion of the 100,000 Genomes Project, Genomics England is now working on various research projects using the data and has also been instrumental in helping to introduce new genomic services into the U.K.’s National Health Service (NHS).

“Repeat expansion disorders are estimated to affect 1/3000 people. Before this study, it was thought to be difficult to diagnose them using whole genome sequencing. Our study validates the use of whole genome sequencing, a newly introduced genetic test in the NHS, to diagnose the commonest form of inherited neurological diseases,” says Arianna Tucci, Medical Research Council Clinician Scientist fellow at Queen Mary University of London and University College London, in a press statement about the research.

The study initially looked at 404 individuals who had previously been tested for the presence of repeat expansion disorders such as Huntington’s disease, fragile X syndrome, or amyotrophic lateral sclerosis. These individuals were referred with suspected repeat expansion disorders and had previously undergone 793 PCR tests.

In comparison to the PCR results, WGS correctly classified 215 of 221 expanded alleles and 1316 of 1321 non-expanded alleles. This resulted in a sensitivity of 97.3% and a specificity of 99.6% across 13 diseases associated areas in the genome.

The team then tested 11,631 people who participated in the 100,000 genomes project who had symptoms of repeat disorders. If WGS indicated a PCR test was used to confirm the result. During this part of the study, 81 repeat expansions were identified. Of these, 68 were confirmed as pathogenic repeat expansions by PCR, 11 as non-pathogenic intermediate expansions or ‘premutations’ and two as non-expanded repeats.

The 68 people who received a confirmed diagnosis, were previously uncertain what was causing their symptoms. One woman, Eileen, was diagnosed with Friedreich’s ataxia during the study.

She said: “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.”

Professor Patrick Chinnery, Clinical Director at the Medical Research Council, added: “Many patients with neurological disorders never receive a precise diagnosis. This new study shows how whole genome sequencing can address this challenge through a genuinely national program, taking world-leading research to patients across the whole of England and improving their health care.”

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