A DROP of mum鈥檚 blood could soon be all it takes to tell whether an unborn baby has Down鈥檚 syndrome. This should reduce, and possibly eliminate, the need for invasive tests that can cause miscarriage.
Currently, women deemed at high risk of giving birth to a child with Down鈥檚 鈥� and who do not wish to do so 鈥� face the tough decision of whether to have an invasive test such chorionic villus sampling (CVS) or amniocentesis. The tests allow women to abort if they don鈥檛 want a child with Down鈥檚, but they carry at least a 1 per cent risk of miscarriage. 鈥淚 can鈥檛 tell you how much parents struggle with that decision,鈥� says Jane Fisher of the UK charity Antenatal Results and Choices in London.
A child with Down鈥檚 inherits an extra copy of chromosome 21 from either their mother or father. Now two research teams have devised blood tests 鈥� that carry no risk of miscarriage 鈥� to detect this extra copy by analysing fetal genetic material shed into the mother鈥檚 blood.
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Though the findings are still preliminary, Dennis Lo of The Chinese University of Hong Kong, who first proposed fetal DNA testing in 1997, is optimistic that far fewer women will need invasive tests for Down鈥檚. 鈥淭his problem really appears to be solvable,鈥� he says.
Lo鈥檚 method, developed in 2007 (Nature Medicine, ), is now being commercialised by the company Sequenom of San Diego, California. The approach focuses on a stretch of chromosome 21 that is only expressed in fetuses. Sequenom looks for the RNA strand that is complementary to this stretch and determines which parent it comes from by identifying single-letter differences in the sequence called single nucleotide polymorphisms (SNPs).
If the amount of chromosome 21 from each parent is roughly the same, the fetus is healthy; but if the quantity from one parent is about double that from the other, the fetus likely has Down鈥檚 (see diagram). So far the company has tested the method in 400 women, of which just 13 turned out to have fetuses with Down鈥檚. However, the RNA test picked up every case and did not flag any 鈥渇alse positives鈥�.
One disadvantage of Sequenom鈥檚 technology, though, is that SNPs vary between populations, so the test may not work outside the US. 鈥淭his is not ready for use in the UK,鈥� says Lyn Chitty, who studies fetal medicine at University College London.
Enter Stephen Quake and colleagues at Stanford University in California. On Monday they reported results from a technique that doesn鈥檛 depend on SNPs. 鈥淥ur approach works on 100 per cent of the population, independent of ethnicity,鈥� Quake says.
The researchers use 鈥渟hotgun sequencing鈥� on short fetal DNA fragments in the mother鈥檚 blood. They then trace each fragment to the chromosome it came from and calculate the proportion from chromosome 21 (see diagram).
The team tested the technique using blood samples from 18 pregnant women 鈥� half with healthy fetuses and half carrying fetuses with Down鈥檚. They found that in the women with Down鈥檚 fetuses, the proportion of chromosome 21 fragments was 11 per cent higher on average (Proceedings of the National Academy of Sciences, ).
Both groups believe their tests have great potential. Sequenom plans to start offering the RNA test to US doctors in mid-2009 after further studies. Though the test won鈥檛 replace invasive methods initially, it should vastly reduce the number of women who need to consider it, says Betty Dragon of Sequenom. 鈥淵ou are putting less children at risk for the invasive procedure,鈥� she says. Quake meanwhile believes the shotgun sequencing approach will make invasive testing obsolete.
鈥淭hough the test won鈥檛 replace invasive methods initially, it should vastly reduce the number of women who need them鈥�
Though Chitty thinks both methods are exciting, she cautions against raising pregnant women鈥檚 hopes just yet. For one thing, the techniques need to be tested on much larger numbers of people. Also, Quake鈥檚 team drew blood samples after the women had undergone CVS or amniocentesis, and some researchers say such invasive tests may trigger the release of fetal DNA, pushing the accuracy of the blood test above what it would be on its own. Quake鈥檚 team dispute this. They say the proportion of fetal to maternal DNA found in their study (about 10 per cent) falls within the normal range.
At the very least, the tests seem likely to be a good way of flagging up women at high risk of having a baby with Down鈥檚 鈥� and so reducing the number who need CVS or amniocentesis. Whether they could be used as the sole means of diagnosis remains to be seen, says Diana Bianchi, professor of pediatrics, obstetrics and gynecology at Tufts University School of Medicine in Boston.
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