Blood test to diagnose Down syndrome

For decades scientists have sought a non-invasive way to diagnose Down syndrome in babies.

Current testing involves amniocentesis, which on very rare occasions may cause miscarriages.

But a new, non-invasive technique for diagnosing conditions such as Down syndrome at as early as 14 weeks gestation and requiring just a blood test has been outlined in new research published in Proceedings of the National Academy of Sciences.

The researchers directly sequenced cell-free DNA with high-throughput shotgun sequencing technology from the plasma of pregnant women.

Using this technique, cases of Down syndrome, Edward syndrome and Patau syndrome were successfully identified in a cohort of 18 normal and aneuploid pregnancies.

We asked New Zealand experts to comment on this latest research.

Donald Love, Director of Diagnostic Genetics, LabPLUS, Auckland City Hospital, and Associate Professor of Molecular Genetics, School of Biological Sciences, University of Auckland, comments:

“The DNA sequencing method described by Fan and co-workers is a technical tour de force and complements other non-invasive molecular approaches that seek to analyse fetal DNA and RNA from maternal blood. It also opens a window on improving our understanding of the very early stages of human development and disease.”

“Parallel DNA sequencing steps up to the mark in quantitating fetal chromosomes from the blood of pregnant women.

“To date, the gold standard for the analysis of fetal aneuploidy such as trisomy 21 (Down Syndrome) involves the microscopic examination of fetal chromosomes derived from the invasive procedures of chorionic villus sampling (in the first trimester) or amniocentesis (in the second trimester).

“The latest sequencing method takes the novel approach of looking at cell-free DNA that is found in the mother’s blood. A small fraction (about 10%) of this total DNA is derived from the fetus. Fan and co-workers undertook parallel sequencing of cell free DNA obtained from approximately 10ml of maternal blood to generate millions of base pairs of sequence in a matter of hours.

“The aim of the sequencing approach was to quantitate the number of sequences that lay on each human chromosome. As reported by Fan and co-workers, a trisomy 21 fetus would yield 50% more sequence “hits” to chromosome 21 than a normal (disomy 21) fetus. The paper reports the successful identification of several trisomy fetuses in a small study of patients who were at risk of fetal aneuploidy.

“This new approach is still research-based but offers the opportunity of detecting fetal aneuploidies as early as the 14th week of gestation in a non-invasive approach.”

Dr Dianne Webster, Director of the National Testing Centre at LabPlus, Auckland City Hospital comments:

“The definitive test in antenatal screening for Down syndrome is a fetal karyotype (analysis of the baby’s chromosomes) on fetal cells obtained by chorionic villus sampling or amniocentesis. Both of these procedures are invasive and carry a small but finite risk to the well-being of the baby.

“Definitive testing is offered to women thought to be at increased risk of having an affected infant. Early identification of women at risk was by age (older women have a  higher chance of having a baby with a chromosome problem, including Down syndrome) but more specific ways of identifying women at higher risk are now used. These are structural markers for example nuchal translucency (the thickness of a skin fold on the back of the baby’s neck) and biochemical markers measured in maternal blood.

“The best performing of these tests can detect about 92% of Down syndrome when 5% of women are offered the definitive test. Scientists have been searching for many years for a non-invasive definitive test and more specific screening tests.

“The paper from Fan and colleagues reports a test with the potential to deliver both of these objectives. They have used state-of-the-art molecular genetics technology (shotgun sequencing) to identify minute amounts of fetal DNA in maternal blood, sorted by each different chromosome, to successfully identify fetuses with trisomies 21 (Down syndrome), 18 and 13. Although all twelve affected pregnancies in the cohort of 18 in the study were identified, these numbers are small and some pregnancies were at a more advanced stage than is possible for screening or definitive testing.

“Larger numbers must be studied to provide better estimates of the sensitivity and specificity of the test. It is not clear that it will be able to identify the subtle, yet important, changes which can be detected by current karyotyping methods (the reason why regular karyotyping is still done even when the faster FISH process is done first).

“The test is still in a research phase. The cost of genetic technologies is reducing dramatically and hopefully by the time the test is sufficiently developed for use as routine screening the price will be affordable. This development is an important step forward and further progress will be watched with interest by antenatal screening systems world-wide.”

Further information

Reference: Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proceedings of the National Academy of Sciences, 2008.
Full-text PDF file of research here

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