A breakthrough in scientific research has found whole genome sequencing can accurately detect some inherited neurological conditions, something previously thought to be impossible. Whole genome sequencing relies on the fundamental truth that all organisms have an individualised genetic code, made up of different pairs of nucleotides (A, T, C, and G). WGS is the unravelling of these unique genetic codes to determine the order of the base pairings. This can facilitate the detection of abnormal gene mutations in relation to neurological disorders.
A recent study explored the diagnostic accuracy of whole genome sequencing to detect neurogenetic repeat expansion disorders. Repeat expansion disorders occur when aa particular gene is continuously and mistakenly duplicated in error. It is thought that around 1 in 3000 people are affected by any one of the 40 known repeat expansion disorders. Examples include: Fragile X syndrome, Huntington’s disease, Friedreich’s ataxia, some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
The first phase of the study assessed the diagnostic accuracy for repeat expansion disorders. They compared the WGS method to the currently used polymerase chain reaction (PCR) test. A sample of 404 patients previously diagnosed using PCR within the NHS were re-tested using the WGS method. They found the sensitivity (97.3%) and specificity (99.6%) of the novel WGS method was comparable to the PCR.
The second phase of the study, again, assessed the diagnostic accuracy of WGS compared to PCR. However, this time the sample consisted of 11,631 people suspected of having a neurological disorder but with no formal diagnosis. The sample was recruited using people already enrolled in the UK’s 100,000 Genomes Project. The WGS method identified 81 repeat expansions which were tested against the PCR. Of those, 68 were confirmed cases of pathogenic repeat expansion, 11 were non-pathogenic (they had repeat expansions but were not harmfully related to a known neurological disorder) and 2 were non-expanded repeats (false positives). Of the 68 who benefitted from a diagnosis was a 10-year-old girl with an intellectual disability and an 18-year-old teenager with dementia.
These findings are encouraging. For those with a family history of genetic neurological disorders and/or presenting with symptoms related to any of these conditions, it gives hope that they can be diagnosed quicker and more efficiently compared to the system currently in use. This is because the PCR is locus-specific (it can only assess one gene at a time) and therefore relies on multiple tests over months, and in some cases years, to build a genetic portfolio encapsulating enough detail for diagnosis. In contrast, WGS can diagnose many disorders in one single test.
The use of PCR is problematic, not least because of the anxiety-inducing waiting time for a diagnosis, but also because the threshold for when repeat expansion disorders become symptomatic varies across people. This means that those with atypical clinical presentations or children without a previous positive family history risk being undiagnosed, a problem that could be greatly reduced through the use of WGS.
Further, researchers would benefit from WGS because it would allow scientists to develop an increased understanding in the frequency of repeat expansion disorders within the population. It would also facilitate an increase in clinical and drug trials to help prevent or delay the onset of these disorders.
This extraordinary research has the potential to reform the diagnostic procedure of inherited neurological conditions within the NHS. Patients and families deserve to have access to accurate and fast diagnosis to relieve them of uncertainty, something this research has shown is, in fact, possible.
Based on: Ibañez, K., Polke, J., Hagelstrom, R. T., Dolzhenko, E., Pasko, D., Thomas, E. R. A., … &Zarowiecki, M. (2022). Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. The Lancet Neurology, 21(3), 234-245.
