Should we sequence everyone’s genome? NoBMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f3132 (Published 21 May 2013) Cite this as: BMJ 2013;346:f3132
- Frances Flinter, professor
This is an exciting time to work in medicine. The enormous advances in our understanding of inherited diseases that have flowed from sequencing the human genome mean that many patients benefit from faster, more accurate diagnoses, targeted screening, cascade testing for relatives, and the availability of prenatal diagnosis and pre-implantation genetic diagnosis. Clinicians see patients, take a family history, examine them, and then decide which tests will confirm or exclude specific diagnoses.
Sequencing the first human genome took 13 years and cost $3bn (£2bn; €2.3bn); today we can sequence a complete human genome in a few days for a few thousand pounds. The price will fall further; however, the cost and challenges of analysing, interpreting, and storing the data are substantial.1 2
Mutation screening within a single gene is rapidly being replaced by targeted screening of a relevant panel of genes known to be implicated in particular phenotypes, and whole exome or whole genome sequencing is likely to become the preferred approach in these situations over the next few years.3 Sequencing data can be filtered so that only variants in relevant genes are analysed; variants that might cause disease can then be validated by functional studies before their pathogenicity is confirmed. In some patients with cancer, detailed genetic studies to identify known variants in DNA extracted from tumours can help to determine the most appropriate chemotherapy—so called personalised medicine.
The UK Genetic Testing Network has led the world in developing a governance framework that ensures proper evaluation of the clinical validity and utility of tests before they are used in clinical practice. The announcement in December that the government plans to sequence the genomes of 100 000 NHS patients in the next three to five years is recognition of the wealth of information that will be revealed. Plans to do this on a research basis, concentrating on the genomes of people with cancer and rare diseases, are sensible, as detailed knowledge of individual phenotypes will support data interpretation, increasing the library of reference information available.4
The PHG Foundation, an independent think tank on the application of biomedical science, welcomed this initiative but identified areas that require clarification before work commences. What will be the nature of the “full and explicit consent” given by patients before their genome is sequenced? What happens if they change their mind? What information will be provided about the results and by whom? How will implications for relatives be handled? What secondary uses of the data will be allowed? How will public trust in health services be maintained in the light of possible commercial gain by the private sector from using the data generated?5
Sequencing the genome of every individual is a very different proposition. Our current, extremely limited, knowledge makes meaningful interpretation of most of the information that would be generated impossible. On average, a normal, healthy person carries about 400 potentially damaging DNA variants plus two variants known to be associated directly with disease traits.6 The figure of 400 is likely to increase as more powerful genetic studies discover rare variants more efficiently. It is difficult to predict the clinical consequences of most of these variants and to prepare individuals to receive this sort of information.7 There would be considerable costs attached to providing additional infrastructure for counselling, imaging, and bioinformatics.8 There are even greater concerns about how people with mental health disorders or learning difficulties could be protected from harm if their genomes were sequenced.9
Privacy cannot be guaranteed, even if data have been entered into supposedly anonymous genetic databases. A recent study showed that it was possible to identify some individuals who had made their genomes available anonymously to researchers by cross referencing genomic sequence data, and other data attached to it, with information available online from recreational genealogy databases. These exploit the fact that short tandem repeats on Y chromosomes are highly heritable from father to son and can be linked to surnames.10
Knowledge may be unhelpful
Individuals may feel fatalistic if they are told they have genetic variants that may predispose them to coronary artery disease, for example, making them less inclined to take steps to protect themselves. We know that 90% of adults at risk of inheriting Huntington’s disease choose not to have a predictive test, preferring not to know their genetic status. For children there is a strong international consensus against genetic testing just for information (as opposed to helping with diagnosis or management of a condition in childhood). For most people, simple lifestyle measures such as eating a good diet, maintaining a normal weight, not smoking, not drinking excessively, and taking regular exercise have far more impact on their health than any genetic variants. Yet it seems remarkably difficult to communicate these public health messages effectively.
If we sequence individuals’ DNA and tell them that they are genetically predisposed to be slightly more at risk of common diseases, we may be doing them a great disservice, demotivating them from behaving sensibly. And the private sector will see a marketing opportunity for all sorts of clinically unnecessary and potentially damaging screening, with further negative and unintended consequences. Possessing the technical ability to do something new is not an immediate justification for going ahead with it, especially in such an ethically complex area. Good medical practice requires tests to answer a specific question with a reasonable expectation of results being interpretable and useful. Currently, whole genome sequencing in healthy individuals has nothing to offer clinically because most of the data generated are meaningless; the maxim first do no harm still holds.
Cite this as: BMJ 2013;346:f3132
As technological prowess soars and costs plummet, is the era of personalised medicine now in sight? John Burn (doi:10.1136/bmj.f3133) says sequencing everyone’s genome would give us unparalleled knowledge to prevent, diagnose, and treat disease, but Frances Flinter thinks there are serious ethical implications
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.
Read John Burn’s side of the debate at doi:10.1136/bmj.f3133.
Provenance and peer review: Commissioned; not externally peer reviewed.