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Whole genome sequencing aids diagnoses of mitochondrial disorders, University of Cambridge study shows

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Another Cambridge study has shown the value of whole genome sequencing to speed up and improve the diagnosis of disease.

University of Cambridge research into mitochondrial disorders showed it picked up 31 per cent more cases than standard tests.

Whole genome sequencing offers more comprehensive data than targeted approaches
Whole genome sequencing offers more comprehensive data than targeted approaches

The research led by the MRC Mitochondrial Biology Unit and Departments of Clinical Neuroscience and Medical Genetics at the University of Cambridge involved 319 families with suspected mitochondrial disease recruited through the 100,000 Genomes Project.

Mitochondrial disorders affect around 1 in 4,300 people and cause progressive, incurable diseases. Although they are among the most common inherited diseases, they are difficult to diagnose, not least because they can affect many different organs and resemble many other conditions.

About 40 per cent of patients miss out on a diagnosis based on current genetic testing regimes.

The study, published in the BMJ, was the first to examine the effectiveness of whole genome sequencing across a national healthcare system - in this case, the NHS.

The method involves analysing the full DNA code to show all genetic differences, or variants, and is therefore more comprehensive than a targeted next generation sequencing approach.

Some 345 participants, aged from birth to 92, had their whole genome sequenced from a blood test. A definite or probable genetic diagnosis was possible for 98 families (31 per cent). Standard tests, which are typically more invasive, failed to make these diagnoses.

A total of 95 different genes were implicated in the disorders.

Researchers were surprised to find 62.5 per cent of the diagnoses were non-mitochondrial disorders and some had specific treatments. This reflected how many different diseases resemble mitochondrial disorders. These disorders would have been missed through standard tests that seek out specific mitochondrial diseases.

Prof Patrick Chinnery, from the MRC Mitochondrial Biology Unit and the Department of Clinical Neurosciences at the University of Cambridge, said: “We recommend that whole genome sequencing should be offered early and before invasive tests such as a muscle biopsy. All that patients would need to do is have a blood test, meaning that this could be offered across the whole country in an equitable way. People wouldn’t need to travel long distances to multiple appointments, and they would get their diagnosis much faster.”

Dr Katherine Schon, from the MRC Mitochondrial Biology Unit and the Departments of Clinical Neuroscience and Medical Genetics, added: “A definitive genetic diagnosis can really help patients and their families, giving them access to tailored information about prognosis and treatment, genetic counselling and reproductive options including preimplantation genetic diagnosis or prenatal diagnosis.”

Some 37.5 per cent of the diagnoses were in genes known to cause mitochondrial disease, and they were nearly all unique to a particular participant family, which reflected the genetic diversity found in these disorders.

Tissues typically impaired by mitochondrial disorders involve those with high energy demand such as the brain, the peripheral nerves, the eye, the heart and the peripheral muscles.

The study provides a valuable new resource for the discovery of future mitochondrial disease genes.

As a result of the study, the team identified potentially treatable disorders in six participants with a mitochondrial disorder and nine with a non-mitochondrial disorder, although the impact of the treatments has yet to be determined.

Prof Chinnery said: “Diagnostic services are fragmented and unevenly distributed across the UK, and that creates major challenges for people with rare diseases and their families. By delivering a national programme based on this genome-wide approach, you can offer the same level of service to everyone."

Dr Schon said: “If we can create a national platform of families with rare diseases, we can give them the opportunity to engage in clinical trials so we can get definitive evidence that new treatments work.”

Last week, the Cambridge Independent reported how a pilot study involving 36 children treated for cancer at Cambridge University Hospitals NHS Foundation Trust demonstrated whole genome sequencing could improve the accuracy of diagnoses and lead to new treatment options. It too was part of the 100,000 Genomes Project, which is designed to help create a new genomic medicine service for the NHS.

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