Scientists in Hong Kong have developed new technology that scans the whole genome of a fetus using cell-free fetal DNA found in the mother’s blood; because it only requires samples of the mother’s blood and the father’s DNA, the breakthrough is a significant step in the development of a single non-invasive test for multiple fetal genetic disorders.

The study, led by Dennis Lo Yuk-ming, professor and Director of the Li Ka Shing Institute of Health Sciences at The Chinese University of Hong Kong (CUHK), appeared online on 8 December in the journal Science Translational Medicine.

In a statement about the research, CUHK said the development is a breakthrough because current prenatal tests are invasive, potentially riksy, and tend to focus on one genetic disorder, whereas this one will hopefully lead to a safe, non-invasive test that screens for multiple genetic disorders.

They said while the technology is still relatively expensive, they expect the costs to fall rapidly.

Current prenatal screening tests include amniocentesis which requires a sample of fluid from the womb, and chorionic villus sampling, which requires embryonic blood taken from a small piece of tissue cut from the placenta.

In 1997, chemical pathologist Lo and colleagues discovered that maternal blood carried cell-free fetal DNA. After that, they decided to establish if it might be possible to use this DNA for a test that scans the whole of the genome of the fetus for genetic disorders.

For the study, Lo and colleagues used blood sampled from a pregnant woman from Southeast Asia.

The first step was to show that the whole of the fetal genome was in fact present in these fetal DNA molecules found in maternal blood plasma, which they accomplished early on, but there was a snag. The DNA was highly fragmented.

Lo told the press that it was like “trying to assemble a jigsaw puzzle that has millions of pieces”.

And added to this was the problem that fetal DNA molecules are surrounded by “an ocean of maternal DNA molecules”.

“This is similar to adding in tens of millions of pieces from another jigsaw puzzle and then trying to re-assemble the first one,” Lo explained.

To achieve this, he and his team had to sequence nearly 4 billion fragments of DNA from the maternal blood sample and do the equivalent of sequencing the human genome 65 times.

In order to help eliminate sequences that belonged only to the mother’s DNA, the team then looked for sequences that carried genetic signatures that were only present in the father’s DNA, and not in the mother’s.

From this they were able to create a map of the fetal genome that had only come from the father.

The more challenging step was to add the next level of information: the fetal inheritance map that had come from the mother, but without it being contaminated with DNA sequences that belonged only to the mother.

This step was more challenging because fetal DNA represents only 10 per cent of the DNA present in maternal plasma, the other 90 per cent is purely the mother’s.

It is in solving this part of the problem that the breakthrough was established: the team developed new technology that detected tiny increases in the maternal plasma concentration of sequences that the fetus had inherited from the mother.

The authors wrote that they also found:

“Plasma DNA molecules showed a predictable fragmentation pattern reminiscent of nuclease-cleaved nucleosomes, with the fetal DNA showing a reduction in a 166-base pair (bp) peak relative to a 143-bp peak, when compared with maternal DNA.”

Using these they could then create the genome map that the fetus had inherited from the mother, add it to the one from the father, and assemble the fetal genome.

Lo and colleagues used the completed map to show that the fetus was a carrier of beta-thalassaemia, a genetic blood disorder that is relatively common in Southeast Asia.

They concluded that:

“Our study suggests the feasibility of using genome-wide scanning to diagnose fetal genetic disorders prenatally in a noninvasive way.”

At this proof of principle stage, the technology is still too expensive to be clinically feasible. There are also other barriers, such as the complexity of the results which are difficult to interpret, said reproductive geneticist Diana Bianchi of Tufts University School of Medicine in Boston in a report on the study by Science Now’s Mitch Leslie.

However, the study has impressed many scientists.

Molecular geneticist Arthur Beaudet of Baylor College of Medicine in Houston, Texas, told Science Now “it’s a beautiful piece of work” and Mark Evans, an obstetrician-gynecologist and geneticist at the Mount Sinai School of Medicine in New York City, described it as an important step towards showing what the approach can do.

“Maternal Plasma DNA Sequencing Reveals the Genome-Wide Genetic and Mutational Profile of the Fetus.”
Y. M. Dennis Lo, K. C. Allen Chan, Hao Sun, Eric Z. Chen, Peiyong Jiang, Fiona M. F. Lun, Yama W. Zheng, Tak Y. Leung, Tze K. Lau, Charles R. Cantor, and Rossa W. K. Chiu.
Science Translational Medicine, 8 December 2010: Vol. 2, Issue 61, p. 61ra91.
DOI: 10.1126/scitranslmed.3001720

Additional sources: CUHK (press release 9 Dec 10), Science Now (“Fetal DNA Sequenced From Mother’s Blood” by Mitch Leslie on 8 December 2010).

Written by: Catharine Paddock, PhD