Published online 6 October 2008 | Nature | doi:10.1038/news.2008.1152


Blood test for Down's syndrome unveiled

Genetic technology used to comb mother's blood for fetal DNA.

pregnancyA blood test could provide a safer way to test a fetus for Down's syndrome.Punchstock

A blood test that uses next-generation sequencing technology could one day replace more invasive methods as a prenatal test for Down's syndrome and other chromosomal disorders, researchers say.

The test has only been tried in a small number of patients, and is years away from daily use in the clinic. But it is one of the first examples of using the recently developed methods for clinical diagnosis. "I suspect there will be many, many more in years to come," says bioengineer Stephen Quake of Stanford University in California, who led the study.

The test relies on finding tiny amounts of fetal DNA that circulate through a mother's blood. Researchers have been avidly pursuing such methods because they could replace invasive procedures such as amniocentesis — in which a needle is inserted into the womb to sample the amniotic fluid surrounding the fetus — or sampling the chorionic villus, a part of the placenta, as both procedures carry the risk of miscarriage.

Circulating fetal DNA is sometimes used to determine the sex of the fetus and to test for certain sex-linked genetic diseases. But developing a test that could look for extra copies of chromosomes, as is the case in Down's syndrome, has proved more challenging. Fetal DNA accounts for only a small proportion of the 'naked' DNA — that not contained within a cell — in the mother's blood. Most lab techniques are not sensitive enough to detect changes in circulating fetal DNA because the signal is drowned out by the mother's DNA.

Alternative approaches

Sequenom, a biotechnology company based in San Diego, California, is already developing a test that looks for differences in the ratio of maternal and paternal sequences in fetal RNA circulating in the mother's blood. If the blood contains twice as much RNA from chromosome 21 of one of the parents, it signals that that the fetus has an extra copy of that chromosome, which causes Down's syndrome.

The company has tested the method in more than 400 patients, and plans to test thousands more by June next year.

Sequenom's method relies on sifting through common sequence differences from the population to find markers that will distinguish chromosomes inherited from the mother from those inherited from the father. Sequenom says that its assays work for more than 93% of the US population.

But those sequences often vary between populations, so the tests may not work on people from different ethnic groups, Quake says. "We decided it's better not to make a choice," he says. "It's better just to sequence everything."

So Quake and his colleagues simply sequenced the circulating DNA en masse, using DNA sequencers made by San-Diego-based biotechnology company Illumina. In the end they did not sequence the entire genome, instead identifying sequences that covered about 4% of each patient's genome.

But that was enough to allow the researchers to pinpoint which fetuses carried extra chromosomes in a group of 18 women. The results are published this week in Proceedings of the National Academy of Sciences USA1.

Next-generation diagnostics

Next-generation sequencing is still a new and expensive technology, says Harry Stylli, Sequenom's chief executive. "Sequencing is way out there," he says. "It is like the Starship Enterprise from a diagnostic perspective."

But Quake, who used to serve on the board of Helicos Biosciences, another next-generation sequencing company, disagrees. "Everybody expects that hospitals will have sequencers sitting there before long," says Quake. "It's a question of when, not if." 

  • References

    1. Fan, H. C., Blumenfeld, Y. J., Chitkara, U., Hudgins, L. & Quake, S. R. doi:10.1073/pnas.0808319105 (2008).
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