The Rare Diseases Genomes Project and Genomics England: by the NHS, for the NHS

Earlier this week, the Rare Diseases Genomes Project was announced, which aims to sequence the genomes of 10,000 rare disease patients in the next three years. This project is a collaborative effort between the University of Cambridge, Illumina Inc. and Genomics England Ltd, and is a pilot project for Genomics England’s 100k Genome Project.

In 2012, the UK government committed £100 million to perform whole genome sequencing on 100,000 people by 2017. To provide focus for the project, Genomics England (GeL), a company owned by the Department of Health, was set up in early 2013. GeL held their first stakeholder meeting earlier this month, to introduce the project to patients, clinicians and other interested parties – including the BHD Foundation.

Sir John Chisholm and Professor Mark Caufield, GeL’s Executive Chair and Chief Scientist, explained that the 100k Genome Project will initially focus on three areas of health: rare diseases, common cancers and infectious diseases. If successful, it is hoped that GeL’s remit will be extended, with the ultimate aim of providing whole genome sequencing as an NHS service.

The 100k Genome Project will take place entirely within the NHS, with qualifying patients being referred to the study by their doctor. Sequencing and genome annotation will be performed at centres contracted to the NHS, and results will be reported back to the patient. Little information is currently available about how patients will be recruited to the Rare Diseases Genomes Project, but GeL are providing 2000 samples to the collaboration, suggesting that at least these samples will be recruited via the NHS.

The benefit of these projects to rare disease patients is substantial. Rare disease patients often face a long and arduous diagnostic odyssey; a recent survey by NORD found that around 20% of respondents waited over a decade for a diagnosis. Professor Patrick Chinnery spoke of the case of two siblings with an unusual muscle wasting disease. Between them, they endured a huge number of tests and over 50 hospital visits spanning 20 years, costing the NHS over £14,000. Whole exome sequencing found compound heterozygous mutations in the SACS gene, took two weeks and cost around £1000 (Pyle et al., 2012). This case demonstrates how sequencing projects can not only be of great benefit to the patient, but can be cost effective for the NHS.

To be eligible for this project, rare disease patients must have a rare debilitating condition that is likely to have a genetic cause. Although mutations in the FLCN gene are known to cause BHD, a small percentage of families with a clinical diagnosis of BHD do not have a FLCN mutation (Benhammou et al., 2011). Whether these families have BHD caused by mutations in an unknown gene, or a different heritable syndrome that is very similar to BHD is currently unknown, but it is possible that any of these families based in the UK might be able to take part in either project, and GeL are keen to work with rare disease organisations in order to find eligible patients.

Whole genome sequencing produces a vast amount of data about an individual, and GeL are mindful of the impact this can have on patients. For example, incidental findings could reveal that the patient is at risk of developing an unrelated serious ailment. There are also likely to be a great number of variants of unknown significance, making clear interpretation of some results difficult. GeL’s advisory group on ethics will ensure that the consent process will allow patients to make a fully informed decision as to whether to participate, and that reporting of the information to patients is clear and consistent.

Due to the large amount of data generated by the 100k Genome Project, collaborations with research to provide additional computational power and expertise will be necessary to make sense of the data. Collaboration is also a key factor in driving the progress of rare disease research, as previously discussed, meaning that opening up this data to rare disease researchers and experts may be of particular benefit to the rare disease patients taking part.

In addition, researchers will be allowed access to the data, anonymised, on application, which might be relevant for epidemiological and drug discovery studies, or to identify patients for clinical trials. However, all analysis will have to be performed within the NHS firewall, with only processed, summary data allowed to be exported, ensuring that patient data is secure.

GeL’s mission to embed genome sequencing within the healthcare system for the benefit of patient health is the only such project in the world, and is largely made possible by the existence of the NHS, which is universal and free at the point of delivery. If this project is successful, it is likely that this will provide a template for other countries to start using whole genome sequencing to improve individual and public healthcare.


  • Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, Wu X, Korolevich S, Nathanson KL, Stolle CA, & Linehan WM (2011). Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome. Genes, chromosomes & cancer, 50 (6), 466-77 PMID: 21412933
  • Pyle A, Griffin H, Yu-Wai-Man P, Duff J, Eglon G, Pickering-Brown S, Santibanez-Korev M, Horvath R, & Chinnery PF (2012). Prominent sensorimotor neuropathy due to SACS mutations revealed by whole-exome sequencing. Archives of neurology, 69 (10), 1351-4 PMID: 22751902

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