More than 10 years after the completion of the Human Genome Project doctors are a step closer to using whole genome sequencing to diagnose and treat patients with genetic diseases. This follows a study by researchers from the University of Oxford and the DNA sequencing company Illumina. Results from this ‘WGS500’ study, published in Nature Genetics, showed that genome sequencing provided definitive diagnoses for up to 60% of patients with some types of genetic disorder, for whom standard genetic testing had previously failed.
The success of this research has already had a dramatic impact in the UK, prompting the government to announce that the NHS will sequence 100,000 genomes for patients as part of the Genomics England programme, with the USA and other countries set to follow suit.
A key aim of the WGS500 study, the largest of its kind to date, was to demonstrate whether genome sequencing results could be widely used by doctors in various specialist departments in a busy hospital setting for the management of their patients.
For the estimated 3.5 million patients with rare diseases in the UK, this technology could transform the diagnosis and treatment of their disease. Sequencing the patient’s entire genome allows all 20,000 genes to be checked at the same time. This would replace the current paradigm of searching for changes in individual genes sequentially, which can take months or years and often fails to give a conclusive result.
Dr Jenny Taylor, a lead author of the study and researcher at the NIHR Oxford Biomedical Research Centre said, "We concentrated on sequencing the genomes of individuals where findings could be immediately useful in terms of diagnosis, prognosis, treatment selection or medical advice for patients and where prior genetic testing had failed to yield results."
To date the study has led to over 10 new disease genes being discovered – for inherited cancers and blood disorders, epilepsy and conditions affecting the muscles or development. This knowledge can help our understanding of why diseases occur and assist in the diagnosis and clinical management of thousands of other patients.
Results of the WGS500 study have already been of immediate clinical use for thousands of patients and their families even beyond those in the study. For inherited colorectal cancers, discovery of two novel genes has enabled doctors to identify family members who would benefit from two yearly bowel screening whilst also helping to reassure relatives who do not carry the deleterious variants in those genes. Globally, 3000 patients have already been tested for mutations in the genes discovered by the Oxford/Illumina study.
The study provided direct examples of how the novel genetic findings influenced treatment for patients. For inherited muscle disorders, selection of the correct medication led to improvement in daily living and reduced use of a wheelchair. For patients with congenital forms of anaemia, an accurate diagnosis enabled interferon treatment to be commenced as an alternative to transfusion- dependence and lifelong unexplained chronic disease.
The study had benefits beyond the medical arena. The clinical identification of the genetic variant underlying their child’s condition proved decisive in the battle by one set of parents in the study to convince their local authority to provide additional educational support for their child.
However, there are still significant challenges to be addressed. Key to the team’s success was the development of novel approaches to analyse the extensive amount of genetic information contained in each person’s genome. Professor Gil McVean, senior author on the study said: "Bringing together the statistical, computational and clinical knowledge needed to analyse and interpret such vast and complex data in real-time is an exciting, but substantial challenge."
Professor Peter Donnelly, Director of the Wellcome Trust Centre for Human Genetics in Oxford, who co-led the study highlighted the tremendous opportunities presented. "Although challenges remain, this study represents an important step in translating the scientific revolution in genetics into improved patient care,” he said. “So whilst the first human genome sequence took 10 years to complete, cost billions and involved thousands of scientists, we can now look forward to the prospect of genome sequences being provided for £1000 and in a few days, for NHS patients across the UK."
Prof Mark Caulfield, Chief Scientist for Genomics England said: "The WGS500 study has been an extremely valuable foundation for the Genomics England’s 100,000 genomes programme, demonstrating that whole genome sequencing can be applied broadly in the clinic for diagnosing patients and informing their clinical management as well as furthering genetic research."
Dr Michael Dunn, Head of the Genetic and Molecular Sciences at the Wellcome Trust, which supported the programme, acknowledged the need for future resources in this arena: "Whole genome sequencing has enormous potential to transform the care of patients in the 21st Century and, as shown in this study, can offer families hope for a definitive diagnosis where standard genetic testing has drawn a blank. However, integrating this kind of individual screening into routine clinical care is not without its difficulties and we will need concerted efforts and resources to enable accurate and meaningful interpretation of genomic data for patient benefit."