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Egenis · News

New, ‘safer’ test for Down Syndrome



Egenis Senior Research Fellow Dr Susan Kelly answers some of the questions the proposed new test raises.


A new, ‘safer’ test for Down Syndrome developed by a research group at Stanford University has been widely reported in the media. The researchers successfully identified nine cases of Down Syndrome from blood samples taken from 18 pregnant women. The new test is one of several approaches scientists are pursuing to develop non-invasive diagnostic tests for Down Syndrome and other abnormalities that are safer and can be conducted earlier in the pregnancy than existing diagnostic tests. The Stanford test analyses fetal DNA circulating in the mother’s blood, and is a novel application of rapid sequencing of the genome made possible by the Human Genome Project. The researchers expect the new test to be clinically available in two to three years. Egenis Senior Research Fellow Dr Susan Kelly answers some of the questions the proposed new test raises.

Don’t we already have tests for Down’s?

Yes we do, but the new tests are seeking to overcome some of the risks and limitations of current testing techniques. Down Syndrome occurs when the fetus’s cells contain three rather than two copies – or ‘trisomy’ - of the 21st chromosome. Prenatal diagnosis is done by counting chromosomes in the fetus’s cells. Standard methods of detecting Down Syndrome prenatally involve screening with a combination of a maternal blood test (looking for specific biochemical markers) and ultrasound (nuchal fold measurement). These screening techniques are not invasive but are not sufficiently accurate to give a definitive diagnosis prenatally. Where a problem is indicated through screening, these techniques would be followed by diagnosis using invasive procedures: amniocentesis after 15 weeks of gestation or chorionic villus sampling (CVS) after 10 weeks. Both of these involve directly sampling fetal cells, and their genetic material, from amniotic fluid or the wall of the uterus. The problem is that the current diagnostic techniques involve some risk of miscarriage or fetal injury, from about 0.05 to 2% depending on the technique and where it is being performed. For this reason, diagnostic tests are offered only to women who because of age, screening or other factors are at a higher risk of a Down Syndrome fetus.

How reliable would this new test be?

A major drawback of current non-invasive methods (blood test and ultrasound) is that they result in false positive and negative findings at unacceptably high levels, and are used to refine a woman’s individual risk of a fetus with Down Syndrome but are not accurate enough for diagnosis. This reliability problem (which means that some women undergo unnecessary procedures, risk and anxiety) is at least partly because the screening techniques don’t directly look at the fetal chromosomes, but rather at other indicators associated with Down Syndrome.

The new non-invasive prenatal test reported by Stanford researchers uses a different method of diagnosing Down Syndrome based on analysis of fetal DNA that floats freely in the blood of a pregnant woman (called ‘cell free fetal DNA’ or ffDNA) and appears at about the 5th week of gestation. There is far less of the fetus’s DNA in a pregnant woman’s blood than her own, making analysis difficult. However, the new technique does not require distinguishing fetal from maternal DNA. It uses a gene-sequencing method to amplify DNA fragments from a specific chromosome, and detects whether there is more of that chromosome than would be expected. For example, excess genetic material from chromosome 21 indicates excess copies of the chromosome from the fetus. New technologies allow measurement of very slight differences in the amount of the chromosome present. The researchers report testing 18 specially selected blood samples, and had 100% accuracy (no false negative or positive results) in detecting pregnancies with chromosomal abnormalities and those without. However, it is still too early to say how reliable the new test would be as further testing on larger samples of women is needed.

The bottom line for any new test is that it must be an improvement in terms of validity, reliability and risk over existing screening and diagnostic techniques.

Could the science behind the test for Down’s be applied to other conditions?

The science behind the new Down Syndrome test is quite innovative and is an example of the clinical application of rapid gene sequencing technologies which are likely to be applied to other types of tests. However, the technique is essentially quantitative – it looks for excess genetic material in the blood indicating extra copies of a chromosome – rather than looking specifically for variations on chromosomes or in genes. So for now the technique would be limited to detecting problems associated with an abnormal number of chromosomes (aneuploidies) but not other types of chromosome abnormalities (e.g., insertions or deletions of genetic material on a chromosome, or swapping of genetic material between chromosomes). Nor can it test for specific genetic variations for single gene disorders.

Another aspect of the science behind this test is that it is based on the presence of ffDNA in the blood of pregnant women. This is a promising area and other prenatal tests using ffDNA for a variety of traits are in use or near introduction. For example, non-invasive ffDNA-based prenatal testing for sex (useful when there is risk of a sex-linked genetic disorder) and fetal blood type (for Rhesus D status) have been in use or in evaluation in a number of locations including the UK for several years. Another group of researchers has developed and is doing further clinical research on a test for Down Syndrome using mRNA. However, that test is only useful in certain populations because it is based on specific genetic changes that are not present universally (e.g., less likely in some population groups). This is not the case with the test we are discussing here; the science on which it is based would be applicable to any population.

The science in the prenatal testing arena is moving rapidly, but no one test that ‘does it all’ non-invasively has yet been developed. The long term goal in prenatal diagnostics is to develop a non-invasive technique for accessing fetal genetic material – preferably the whole genome – for genetic analysis. This would allow testing for single gene disorders as well as chromosomal abnormalities, and for other conditions for which genetic associations have been identified. Should such a non-invasive vehicle for genetic testing be developed and be highly reliable, it will certainly open debates about its introduction into clinical practice, and about how, when and for which conditions it should be used. There are currently genetic tests on the market for conditions ranging from diabetes to bipolar disorder to athletic ability! However, whole fetal cells in the blood of pregnant women are rare, and such a test is some way in the future. (On the horizon is a test through which fetal cells are obtained by cervical swab, like a PAP smear, but again this is some way off.)

Is this good news for all prospective parents?

Some prospective parents who would not seek a Down Syndrome diagnosis because of the physical risks might do so when offered a non-invasive test. While some prospective parents might chose to terminate an affected pregnancy, others may want definitive information in order to prepare for the birth. Some infants will require immediate medical attention, and some prospective parents may want to line up therapies and other forms of care before the birth.

Non-invasive prenatal genetic testing raises a host of questions, however. Currently, the fact that a small risk exists requires prospective parents actively to weigh those risks against the benefits of the information. For some people this is fairly straightforward, but for others it involves quite a bit of soul searching. There is some fear that the reduction of physical risk would result in the test being handled less seriously, and prospective parents would receive less information about the implications of testing, Down Syndrome and parenting an affected child. And informed consent is a real issue – blood tests are quite routine in prenatal care, and women are not always aware of every test that is being run on every sample (for example, HIV testing).

Since March 2008, guidelines from the National Institute for Health and Clinical Excellence (NICE) recommend that all pregnant women be offered an ultrasound anomaly scan and a blood test for Down Syndrome during the first trimester. If the non-invasive test is found to be accurate and reliable, it may be the case that all pregnant women will be offered a diagnostic test for Down Syndrome. Since prenatal screening for Down Syndrome has become routine and offering it the standard of care, there is concern that women feel pressure to accept screening whether they really want the information or not. Similarly, a non-invasive diagnostic test might put women under pressure to terminate a pregnancy whether they have considered the implications or not.

There is the potential for blood to be tested without consent – for example, one can envision circumstances where a third party, such as the state or a guardian, may have an interest in prenatally diagnosing a condition such as Down Syndrome. With the increasing availability of genetic testing over the internet, direct to consumers, it may be difficult to control the origin of the blood sample sent in, and to ensure that tests are accompanied by appropriate counselling. Already, a company in the United States offers a non-invasive sex selection test over the internet.

Is everyone in favour of prenatal testing?

Prenatal testing has become routine in spite of remaining controversial. Certainly there are arguments against prenatal testing that are made more urgent by the introduction of non-invasive diagnostic testing. Some people are not in favour of prenatal testing because at present, most conditions that can be tested for cannot be treated or cured, and prospective parents face the option of terminating an affected pregnancy. This is an option that some people find objectionable. There has been opposition to prenatal testing from some disability rights activists, and from parents and family members of people affected with conditions such as Down Syndrome. They are concerned that increased ease of testing for Down Syndrome will lead to fewer people with the condition being born, and thus less provision of the services and support needed for people with Down Syndrome to live more independent and socially integrated lives. There is also concern that prospective parents are not given sufficient accurate information about conditions such as Down Syndrome and how it affects both the child and the family. The Antenatal Screening Web Resource (AnSWer) initiative in the UK has been established to help provide prospective parents with this information.

I and other researchers in this area have found that some parents face prenatal testing with a great deal of ambivalence, particularly when they have some experience with disability.

Is this a (further) step towards ‘designer’ babies? Should we really be trying to screen out any trait parents see as undesirable?

This particular test doesn’t really take us further toward designer babies, but rather makes it safer to test for a condition that is already the major focus of prenatal screening. And this is true of many of the other ffDNA-based tests being evaluated. However, this is a conversation we will need to have at some point in the future, when non-invasive tests for a wide range of genetic conditions become available. Non-invasive prenatal testing for fetal sex is already available, and as a society we haven’t really had that kind of conversation about sex selection yet. Prospective parents who currently want to ‘screen out’ particular traits can do so with preimplantation genetic diagnosis, although that is far from a simple process. The increasing availability of direct to consumer tests over the internet is creating pressure to keep such tests in the commercial realm, where individuals make their own decisions about what is trivial and what is important. Certainly some ethicists point to a slippery slope, arguing that tests introduced for serious conditions will come to be used for those considered more trivial. Again, however, it would not be easy to come to societal consensus about what is ‘serious’ and what is ‘trivial’, or to draw a line between medical and social reasons for undesirability. There will be limits to how the use of non-invasive prenatal tests can be regulated, as well as debates about whether or not they should be.

In the UK, will the NHS automatically pay for new prenatal tests?

This is an interesting question. The NHS will not automatically pay for the new test when it becomes available, and it would likely go through an evaluation process before being provided by laboratories in the UK. The Human Genetics Commission discussed non-invasive prenatal testing based on ffDNA at a meeting in February 2008, and testimony to the Commission revealed that the NHS, in some centres, is currently paying for other forms of ffDNA testing that are being evaluated for identifying fetal sex and diagnosing single gene disorders. At least one centre in the UK offers a form of ffDNA testing as a service, outside a research context, and the transition from evaluation to service is somewhat murky. The Genetics Commission Advisory Group (GenCAG) has an overall remit to take a national strategic overview of genetic services, and the UK Genetic Testing Network (UKGTN) recommends new genetic tests to be funded, but laboratories may offer specialised testing and the final funding decision rests with the Primary Care Trusts.

In theory, a new test such as this would be compared against currently available services. It will also be important to examine costs to the health system beyond the test itself, including a wide range of implementation issues.