For certain sex-linked genetic diseases reliable determination of fetal sex can indicate whether or not the fetus is at risk; for example, in families affected by Duchenne Muscular Dystrophy, male fetuses may develop the disease, but female fetuses will not. In a few cases, identification of an affected fetus allows treatment to prevent or limit the disease. Where this is not possible, the aim is to provide women with the opportunity to make a suitably informed choice about an affected pregnancy; some opt for termination, whilst others prepare for the birth of a child with a disease or abnormality, which may include dealing with emotional/psychological issues and making plans for appropriate medical care of the newborn.
However, to perform a definitive diagnosis, doctors must use an invasive technique to sample fetal DNA directly, either from the placenta (chorionic villus sampling, or CVS) or the amniotic fluid around the fetus (amniocentesis). Unfortunately these procedures carry a risk of miscarriage of around 1%. Several hundred healthy pregnancies are lost in the UK each year due to invasive testing; many women decide against testing for this reason, but then have to go through the whole pregnancy without knowing whether or not their child is affected. A non-invasive means of testing would therefore be hugely preferable.
In the last ten years a new technique has emerged to extract and analyse cell-free fetal nucleic acids (DNA or the related molecule RNA) from maternal blood, potentially allowing non-invasive prenatal diagnosis of a range of genetic conditions as well as identification of fetal sex and blood group status. Not only is this approach safer than current invasive approaches, but it can also be performed much earlier in pregnancy, from as little as 5-7 weeks, making it a highly desirable tool for antenatal-related services, some of which are actively developing the technique.
A number of technical difficulties remain. The major problem is in accurately distinguishing between the maternal and fetal DNA; the latter represents only a very tiny proportion of the DNA present in the maternal blood, and so a unique fetal characteristic (or marker) must be used to selectively extract the few fetal molecules from the background of maternal ones. The most obvious of these characteristics is sex; if the fetus is male, then fetal DNA can be recognized by male-specific (Y-chromosome) sequences.
However, the main requirement is for a sex-independent, fetal specific marker that can distinguish the DNA or RNA of male or female fetuses from that of the mother; for example, genes expressed only by the placenta. For the diagnosis of specific single-gene (Mendelian) disorders, the need is for a unique fetal marker that will simultaneously identify DNA or RNA as being fetal in origin, and contain the necessary sequence for diagnostic analysis. A different approach is required to reliably identify large-scale, chromosomal abnormalities such as aneuploidies, where the fetus has either too much or too little chromosomal material present (for example, Down Syndrome is caused by the presence of an additional, third copy of chromosome 21 in the cells of the fetus).
Even when these requirements have been successfully addressed, there remain limitations to free fetal nucleic acid analysis; for example, genetic diseases that involve large expansions of regions of the DNA are not amenable to diagnosis in this manner. Ultimately though, it is hoped that this new non-invasive technique will allow improved (safer, earlier and cheaper) antenatal screening for many serious genetic diseases. As a further development it is also hoped that it may enable doctors to monitor pregnancies much more effectively for serious complications that can affect the health or survival of both the fetus and the mother, such as pre-eclampsia, intrauterine growth restriction or premature labour. Detecting changes in the levels of fetal nucleic acids in the maternal blood could provide early warning of such conditions well in advance of the appearance of clinical symptoms in the mother.
This novel approach to antenatal screening and diagnosis inevitably raises some associated social and ethical issues, as discussed in the accompanying commentary by ethicist Ainsley Newson; for example, the potential to determine fetal gender early in pregnancy for social (as opposed to medical) reasons via commercial providers, or the possibility of offering routine diagnosis (as opposed to initial risk assessment) of Down Syndrome for all pregnant women. For this reason, the PHG Foundation is working with different stakeholders in this field (including representatives from the medical, scientific, patient and policy communities) to ensure that technical innovation in this area is effectively transferred into clinical practice in a swift but appropriate manner.