Antenatal diagnosis of Down's syndrome from mother's blood

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22 October 2008
Down's syndrome is a genetic disorder caused by an extra copy of chromosome 21. The syndrome affects physical appearance and the speed with which mental, physical and social skills are acquired. In the UK, about 600 babies with Down's syndrome are born each year. Although the chance of having a baby with the syndrome increases with the mother's age, over 80% are born to women under 35 because there are more births at this age.

In the early weeks of pregnancy maternal screening can help assess the risk of the baby having Down's syndrome. Only a proportion of women with a result in the higher risk category will have an affected baby. To make a firm diagnosis so that a mother can decide whether to continue with the pregnancy it is necessary to test baby's cells taken either from the placenta (chorionic villus sampling) or from the fluid around the baby in the uterus (amniocentesis). Both sampling procedures carry the risk of causing miscarriage in a small number of cases. Clearly, a non-invasive test that can give a definitive answer is highly desirable.

In 1997 YM Lo and colleagues working in the University of Oxford reported in the Lancet that baby's DNA could be detected in mother's plasma and suggested that their finding might have implications for non-invasive prenatal diagnosis. There have followed years of intensive research to separate the mixture of mother's and baby's DNA fragments in mother's plasma. At the present time the sex of the baby and its Rhesus (RhD) blood group in RhD-negative mothers can be determined reliably from the mother's plasma, both testing for DNA sequences completely absent from the mother's chromosomes. DNA tests have also been developed that are better at predicting the risk of Down's than conventional maternal screening. However, because there are variations in chromosomal DNA sequences in different ethnic groups, none is reliable enough to replace the invasive tests.

A promising new approach that can be applied to all populations and races was published online by research workers from Stanford University in the Proceedings of the National Academy of Sciences on 6 October 2008. In Down's syndrome there is an extra copy of chromosome 21, so the workers argued that it might be possible to detect an increased number of fragments of DNA derived from that chromosome in the mixture of mother’s and baby’s fragments in the mother’s plasma without having to separate them. A new analytical technique which allows massive parallel sequencing of DNA fragments was used to produce tens of millions of DNA sequences in a single run. Using a powerful computer program the first part of each sequence (25 base pairs) was then ‘mapped’ to the chromosome map developed by the Human Genome Project, and the 'relative density' of chromosomes calculated.

The report gives the results of this 'shotgun' analysis of plasma samples from nine women with Down's pregnancies (eight in their 14th to 25th week, one at 35 weeks) and nine women without Down's pregnancies in their 10th to 23rd week. Each of the Down's pregnancies had more DNA fragments from chromosome 21 than the other pregnancies. Three of the others carried babies with extra copies of a different chromosome. These were also clearly distinguished, both from the Down's and from the six normal pregnancies.

The study's senior author, Stephen Quake, Professor of Bioengineering at Stanford University, said the test should provide a safer and earlier diagnosis for Down's than the invasive tests, of benefit both for those who decide to keep and those who decide to terminate their pregnancies. Their next step is to repeat the study in larger numbers. If the results are successful, he hopes a relatively inexpensive clinical test will become available within two or three years.