IntroductionEgenis Senior Research Fellow Dr Susan Kelly reflects on the current state of prenatal genetic diagnosis.
A study reported in the British Medical Journal (BMJ) suggests that a DNA blood test for Down Syndrome could save nearly all pregnant women from invasive tests like amniocentesis. Specifically, the scientists report techniques for diagnosing Trisomy 21 (causing Down Syndrome) with sufficient accuracy to obviate the need for some 98 per cent of invasive diagnostic procedures (writes Dr Kelly). The study follows hard on the heels of a report in Science Translational Medicine by the research group of Dennis Lo, from the Chinese University of Hong Kong, that whole fetal genome sequences are retrievable for analysis from the circulating blood of a pregnant woman. This is a new milestone in the rapidly developing field of prenatal genetic diagnosis.
In 1997, the same group reported finding fetal DNA fragments circulating in maternal blood and demonstrated techniques for analysing these sequences for a limited range of conditions. The new findings brought a new angle to this research, suggesting that, in conjunction with rapid advancements in next generation sequencing technologies, a whole genome scan of a developing fetus could become feasible in the relatively near term. And the new technologies promise earlier results, perhaps reducing a the difficulty of bonding with and then losing a pregnancy, and allowing women and couples to make decisions about termination earlier than is currently possible. Next generation sequencing machines allow faster, cheaper and ‘deeper’ sequencing, meaning that much more genetic information can be gained, at much lower cost, and with ever increasing accuracy. With the capacity to obtain such information from an easily and safely obtained blood sample, the nature of prenatal testing and care may well be significantly changed.
The research reported in the BMJ confirms that if maternal blood could be routinely screened, invasive procedures such as amniocentesis could be avoided in most cases. Does this take us closer to the scenario of designer baby-like choices, or merely improved prenatal health care? The answer is probably both, and neither, at least in the near future. History suggests that clinical applications will lag behind expectations. It also suggests, however, that now is the time to start taking the future possibilities of prenatal whole genome scanning seriously and to being to plan for its implications.
Obstetric care has witnessed the steady refinement of existing techniques for screening the fetus for conditions such as Down Syndrome. These screening techniques provide increased ‘risk’ information without being diagnostic, that is, without being 100% accurate. And yet, facing the prospect of making difficult decisions on the basis of this information has become a routine part of the package of pregnancy care for women in many parts of the world. From a health provider point of view, these tests provide potential parents with important information that can lead them to seek a definitive (although slightly risky) diagnosis, prepare for a difficult birth, and get necessary medical and social support in place before the birth. The pros and cons of these procedures have occupied clinicians, social scientists and bioethicists for decades, as well as being experienced by patients, but there has been some comfort in the known limits of these technologies. The spectre of a society of ‘designer babies’ has remained beyond our capabilities, a science fiction.
It is not at all clear that findings of accessible whole fetal genomes in maternal blood will take us rapidly toward this future, a society of unlimited choice. To begin, the information obtainable from a whole genome scan is limited by what we can and do know about the genetic variations we all carry. Studies of the genomes of very large samples of people, called genome wide association studies (GWAS), are finding that a large number of genetic variants contribute a small amount to the risk of most diseases or conditions studied. The simple ‘gene-for’ view of genetics is highly oversimplified. Genetic variants may contribute to the onset of disease, but in many cases we just don’t know precisely how. Further, each one of us will harbour some of these disease variants, even for quite serious conditions, and yet remain unaffected throughout our lives. Some of us may enjoy knowing such information, available commercially through a range of companies over the internet, and yet few of us will make meaningful life changes on the basis of that knowledge. This also means that efforts to ‘select’ or remove traits in our children on the basis of genes may well fail to produce the desired result, in an unknown number of cases.
The task of interpreting such vast amounts of data far outstrips the capacities of health professionals to adequately interpret, inform, counsel and guide, potential parents through the choices even the highly selective application of whole genome sequencing to routine pregnancies may raise. It appears likely that in the near future it will be cheaper to sequence the entire genome of a patient than to conduct a test for a single genetic abnormality. This inevitably raises the problem of incidental findings – with a whole genome scan, genetic variants that were not the focus of the investigation will be identified. What are health professionals to do with this information? What are their duties to patients, what are patients’ rights, and how will the consequences of either providing or withholding such information be handled? What will people want to know?
A likely scenario would involve the maintenance of prenatal whole genome scanning information in a database for future analysis. Who will have access to such information? What sorts of protections will need to be crafted, and in what regulatory regimes?
There are, of course, a number of reasons to project that prenatal whole genome sequencing may impact reproductive medicine in more incremental, and less dramatic, ways. Currently, researchers in a number of countries including the UK, US, the Netherlands, and China, are pushing ahead with the refinement of non-invasive tests for Down Syndrome. Although it is not clear precisely how the tests under development will be implemented in clinical practice, it is likely that they will be available within the next three to five years. Already, these technologies are greeted with enthusiasm by some health professionals, but resistance by others. It is not clear that even limited changes will be easily accepted in health care contexts. The accuracy and clinical usefulness of a technological change with this kind of disruptive impact will receive considerable professional scrutiny, as will the resource implications of changes in practice.
Those health systems that, unlike the United States, have more direct control over the introduction of innovative health technologies will no doubt be analysing costs of different scenarios of introduction. Such projections must take into account the costs of training health care workers, interpreting and managing information, counselling, and organisational changes involved in implementing new clinical pathways. These analyses will take time, and will be accompanied by further time consuming deliberations about regulation and professional care standards. These and other necessary social accompaniments to technological change will ensure that the Lo team’s findings will not enter clinical practice for some time.
Prenatal testing represents a significant market for industries involved in or related to DNA-based diagnostics. The availability of genetic tests directly to consumers over the internet, and through private providers, continues to develop. Although various national regulators are responding to the challenges of the DTC genetic testing market, the real constraints these measures can affect have yet to be seen. The global nature of this industry may confound such efforts in the long run. Will worried prospective parents who have obtained prenatal genomic sequence information in the private sector seek definitive answers about their health implications from under-resourced public health care systems? The limited social science research to date on direct to consumer intentions concerning privately accessed genetic testing information supports this scenario.
There are positive clinical scenarios as well, of course, and these will drive the development of these technologies as they are currently driving other non-invasive prenatal diagnostic approaches. Access to the whole fetal genome will allow prenatal diagnostic testing of a wider range of genetic conditions, potentially providing many prospective parents better outcomes in difficult reproduction contexts, and will overcome some important limitations of current and emerging testing approaches. Cell free fetal DNA findings have led to improved clinical management for some sex-linked conditions, some single gene disorders, and in some countries, maternal-fetal blood incompatibility.
There are reasons to be both optimistic and pessimistic about what follows from the findings of analysable whole fetal DNA in maternal blood during pregnancy. But now is the time for the medical community to think through what this future might hold for their patients, their professions, and the health systems in which they work. What is the value, and the utility, of whole genome sequence information in the prenatal context? How will the significant interpretive tasks associated with such information be addressed? How will the extremely important issues of patient, and professional, education be managed? How will incidental findings be handled? How will the sensitive relationship between public and private economic interests in a widely applicable technology be affected? And more broadly, in what ways may these technological advances affect the experience of pregnancy and pregnancy care, in all of the contexts in which they are received?
Reproductive health care has long been the area of medicine where most people are likely to come into contact with genetics, and it is not surprising that significant and potentially transformative achievements in genomics are ‘sneaking up’ on us from this direction.