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A ground-breaking technology for scanning the entire genome of a fetus non-invasively from a blood sample obtained from its pregnant mother developed by a research team led by Professor Dennis Lo Yuk-ming, Director of the Li Ka Shing Institute of Health Sciences at The Chinese University of Hong Kong (CUHK), was reported in the latest issue of the premier biomedical journal, Science Translational Medicine.

In 1997, Professor Dennis Lo and his co-workers discovered the presence of cell-free fetal DNA in maternal blood plasma. This discovery has opened up new possibilities for non-invasive prenatal diagnosis, reducing our reliance on conventional invasive, potentially risky, methods of prenatal diagnosis, e.g. amniocentesis. Since then, this technology has been used by many researchers and diagnostic laboratories around the world, with testing typically focusing on one disorder, e.g. Down syndrome, at a time. The new research reported in Science Translational Medicine represents a quantum jump over the previous state-of-the-art in the field as it allows multiple disorders on a genome-wide scale to be scanned in one test. 

To investigate if such a test is scientifically possible, Professor Lo and his colleagues had to first demonstrate that the entire fetal genome was present in maternal blood plasma. After an affirmative result was obtained, the research team then went on to develop the technology needed for a non-invasive fetal genome scan. This task is very challenging because the DNA molecules in blood plasma are highly fragmented. Professor Lo says, “It is like trying to assemble a jigsaw puzzle that has millions of pieces. To make matters worse, the fetal DNA molecules in the pregnant mother’s blood plasma 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.”

To achieve this task, the research team sequenced nearly 4 billion DNA fragments from the maternal blood sample. This was equivalent to some 65-fold coverage of the human genome. They then searched the sequencing data for genetic signatures that were only present in the father, but absent in the mother, of the fetus. Taking these signatures together, the team then built a genetic map of sequences that the fetus had inherited from its father. 

The building of the fetal inheritance map from its mother was much more challenging as fetal DNA represented only some 10% of the DNA in maternal plasma. The remaining 90% consisted of DNA from the mother herself. To solve this problem, the research team had developed a new technology that would allow the minute increases in the concentration of sequences that the fetus had inherited from its mother to be detected in maternal plasma, and thus constructed a fetal inheritance map from the mother. 

By combining the paternally-inherited and maternally-inherited genetic maps, CUHK researchers were able to arrive at a genomic map of the fetus. The research team then used the map to show that the fetus was a carrier of beta-thalassaemia, a relatively common genetic blood disorder in Southeast Asia. 

This important development has laid the foundation for a new generation of prenatal tests that can detect multiple genetic disorders that are common in a particularly geographical area. While this technology is still relatively expensive at present, it is expected that costs will rapidly come down.