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At the annual meeting of the Association for Molecular Pathology this week, the Chinese University of Hong Kong's Dennis Lo spoke about bringing non-invasive prenatal diagnostic testing to the clinic, using next-generation sequencing. Although it is now routine in many parts of the world to test for X-linked disorders, some women choose to undergo invasive prenatal diagnostic testing for Down syndrome, Lo said. Testing for Down syndrome using the mother's blood is more challenging than testing for X-linked disorders in that manner is. That's because the trace amounts of fetal DNA are detectable in the mother's plasma, but it's difficult to determine which of the maternal DNA in a plasma sample is from the mother, and which is from the fetus, Lo said.

When taking a sample of the mother's blood, about 95 percent of that DNA will be the mother's and 5 percent will be from the fetus, Lo said. In a sample with 1,000 genome-equivalents per milliliter, that would mean a total of 1,900 maternal chromosome 21s, and 100 chromosome 21s for a euploid fetus and 150 chromosome 21s for a fetus with Trisomy 21. If a diagnostician is to count a difference of 50 chromosome 21s in a DNA sample, he needs to count hundreds of thousands of molecules to increase the discrimination power, Lo said. And with next-generation sequencing, it is indeed possible to count hundreds of thousands, even millions, of molecules.

Using this method, Lo and his team showed they were able to determine whether a fetus had Down syndrome as early as 11 weeks with 100 percent accuracy, with only a sample of the mother's blood. Several studies released since then, by Lo's group and others around the world, show that next-generation sequencing can be used to diagnose Down syndrome in a fetus with sensitivity and specificity upwards of 90 percent.

Lo said his studies showed that if you sequence at least 10 million molecules per case, you can obtain high sensitivity to tell if a fetus has Down syndrome. In terms of cost, it's entirely doable, he added. An Illumina HiSeq machine can sequence a billion reads per run — if you assume one run per week, that means 5,000 cases a year can be tested, Lo said. In Hong Kong, which has a population of about 7 million, one machine would be more than enough for the entire city, and could even be used as a first line test for Down syndrome, he added.

And the technology could probably be pushed further. Lo and his team have shown that the entire fetal genome can be sequenced and searched for deleterious mutations using a quantitative approach. For now, such testing would be prohibitively expensive — Lo and his team had to sequence the DNA at 4,000x coverage in order to separate the fetus' DNA from the mothers, and the experiment cost $420,000 for one case. But, Lo said, it may be possible for someone to come up with a fetal sequencing test that could be done in the clinic down the line. Next-gen sequencing can be an effective non-invasive prenatal diagnostic tool, he added.