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Whole-Genome Sequencing Can Diagnose Neurological Repeat Expansion Disorders, UK Study Finds

NEW YORK – Researchers in the UK have demonstrated the ability of whole-genome sequencing to outperform conventional methods for detecting neurological repeat expansion disorders, making the case for WGS to be used as a routine diagnostic test for patients suspected to have such a condition.

The study, published in The Lancet Neurology on Wednesday, involved researchers from Queen Mary University of London, University College London, Illumina, Genomics England, and National Health Service England.

Repeat expansion disorders are clinically heterogeneous diseases that affect about 1 in every 3,000 people and are caused by expansions of short tandem DNA repeats. Examples of such disorders include fragile X syndrome, Huntington’s disease, Friedreich's ataxia, and some forms of amyotrophic lateral sclerosis.

Testing to date has relied on PCR to assess specific genomic loci in patients, but, as the authors note, this has resulted in an underdiagnosis of patients with atypical presentations, or lack of family history. As NHS England has already been relying on whole-genome sequencing as a first-line test for diagnosing rare disorders, the researchers decided to focus on this group of disorders for their project.

In the study, they retroactively looked at the accuracy of whole-genome sequencing to detect the 13 most common repeat expansion loci associated with neurological outcomes, using samples from NHS patients thought to have neurological disorders who were recruited between 2013 and 2017 as part of the 100,000 Genomes Project. They used earlier PCR test results for the loci in 404 patients as a reference standard. When whole-genome sequencing of patient samples resulted in a repeat expansion call, they used PCR again to confirm those calls.

According to the authors, whole-genome sequencing showed 97.3 percent sensitivity and 99.6 specificity for detecting repeat expansions across the 13 loci, compared to PCR results.

The authors also looked at samples from 11,631 undiagnosed patients with suspected repeat expansions, based on their clinical features, from the 100,000 Genomes Project. They were able to tag 81 repeat expansions in these, 68 of which were in the full pathogenic range providing these patients with a diagnosis.

"These findings support implementation of whole-genome sequencing in clinical laboratories for diagnosis of patients who have a neurological presentation consistent with a repeat expansion disorder," the authors concluded.

They noted that individuals with these disorders tend to have a long journey to diagnosis, requiring various tests. Based on their findings, whole-genome sequencing could replace the use of multiple tests to reach a diagnosis for patients.

"At the moment, diagnosing this type of neurological disorder often depends on people having a family history of the disease or specific clinical symptoms," said Mark Caulfield, a professor at Queen Mary University of London and former CSO at Genomics England. "[U]sing whole-genome sequencing, we can detect these and new repeat expansion disorders."

Caulfield said the study "represents a major advance in the application of whole genomes, enabling detection of previously unexpected inherited neurological disorders."