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Whole Genome Sequencing Shown to Detect Neuro Disorders

DNAmolcule model

(Skeeze, Pixabay)

17 Feb. 2022. An analysis of genetic database records indicates a class of neurological diseases can be detected by sequencing of a person’s entire genome. Results of a study by researchers from Queen Mary University of London, genomic systems company Illumina, University College London, and Genomics England appear in today’s issue of the journal The Lancet Neurology.

A team led by neuroscientist Arianna Tucci with Queen Mary University and Genomics England, and vice-president for scientific research at Illumina Ryan Taft, seeks to find accessible and reliable methods for detecting repeat expansion disorders. These conditions result from expansions of simple sequence repeats, where base pairs of amino acids in DNA are repeated several times in tandem. More than 40 inherited or genetic diseases mainly affecting the nervous system are linked to repeat expansion, including Huntington’s disease, Friedreich ataxia, and fragile X syndrome. The authors cite data indicating repeat expansion disorders affect about 1 in 3,000 individuals.

One method for diagnosing inherited diseases is genomic sequencing that analyzes the order of base pairs making up DNA to identify disease-causing variations. In most cases, however, diagnostic genomic sequencing looks for a particular variant in DNA. Detecting an entire class of genetic disorders would require conducting many of these tests, a highly inefficient and expensive process.

In this study, researchers investigated the feasibility of whole genome sequencing to detect repeat expansion disorders. Whole genome sequencing is made possible by advances in sequencing technology that enables faster throughput and analytics to parse and reassemble the entire genome at a reasonable cost. Illumina in San Diego, a partner in the study, is a developer of genomic analysis systems, including whole genome sequencing.

Whole genome sequencing compared to PCR tests

The team analyzed genomic sequencing data stored in the 100,000 Genomes Project undertaken by Genomics England, a genetics research initiative funded by U.K.’s National Health Service and others. The project sequenced 100,000 genomes of some 85,000 U.K. residents with cancer or rare diseases through 2018, with data now made available for researchers. In this case, the study team looked for people with indicators of repeat expansion in samples from the 100,000 genomes database, and then compared the analysis to standard polymerase chain reaction or PCR diagnostics for neurological disorders in linked NHS medical records for identified individuals.

The team first analyzed the genomes of 404 persons with neurological disorders, identified by PCR diagnostics in their medical records. The results show whole genome sequencing identified 215 of 221 repeat expansion variations that match PCR diagnostics, with a true-positive sensitivity of 97 percent. Whole genome sequencing also correctly identified 1,316 of 1,321 non-repeated variations, with a true-negative specificity of 99 percent.

Researchers then sampled whole genomes of 11,631 participants in the 100,000 Genomes project. The data identified 81 cases of repeat expansions from the genomic records, and later confirmed as disease-related in 68 of those cases with PCR analytics. Of the remaining repeat expansions, 11 cases were not disease-related and two cases were found not to be expansions.

The authors conclude that implementing whole genome sequencing is a feasible diagnostic tool in cases where repeat expansion disorders are suspected. “This study demonstrates,” says Taft in a Genomics England statement, “that whole genome sequencing can be used in clinical laboratories for the diagnosis of patients who have a neurological disorder, such as Huntington’s disease. For the large percentage of patients with suspected repeat expansion disorders who remain undiagnosed, this should bring hope that a diagnosis may soon be possible.”

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