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Circulating Fetal Nucleic Acids

Circulating Fetal Nucleic Acids

The group led by Professor Dennis LO at the Department of Chemical Pathology is a global leader and pioneer in non-invasive prenatal testing (NIPT). This group has elucidated the fundamental biological characteristics of circulating cell-free fetal DNA in maternal plasma, e.g. its concentrations, size characteristics.


The most impactful research achievement to date was the successful development of non-invasive prenatal screening for Down syndrome based on cell-free DNA analysis in maternal plasma. Conventional screening methods for Down syndrome, such as maternal serum biochemical markers and fetal ultrasonography, are associated with relatively high false-positive rates. This has led to a high number of invasive prenatal diagnostic procedures being performed, such as amniocentesis, which far exceeded the number of fetuses with Down syndrome. In this project, we have successfully developed maternal plasma cell-free DNA tests that offered 99% sensitivity at 0.1% false positive rate for the Down syndrome screening. The efficacy of the test approach was recognised by professional organisations, such as the American College of Obstetricians and Gynecologists, American College of Medical Genetics and the International Society of Prenatal Diagnosis, which recommended the incorporation of NIPT into routine prenatal practices. Technology transfer arrangements between CUHK and companies such as Sequenom and Illumina were established. To date, NIPT for fetal chromosomal aneuploidy screening is practised in over 90 countries and has led to a worldwide reduction in the number of invasive prenatal procedures performed. The team has also developed maternal plasma DNA-based approaches for the non-invasive screening of other fetal chromosomal and subchromosomal aneuploidies.


The World Health Organization (WHO) has estimated that the collective incidence of single gene diseases is about 10 in 1,000 pregnancies. The non-invasive detection of single gene disease mutations by cell-free fetal DNA analysis is challenging because there is a large number of single gene diseases and each disease may be associated with a myriad of gene mutations. Point mutations in particular are challenging to detect in maternal plasma. The team proposed that much of the technical challenges could be overcome by using single molecule counting strategies. The team developed a number of strategies which have been adopted for clinical use in centres around the world.


To maximise the amount of information of the fetus that could be extracted from maternal plasma analysis, the team has successfully developed non-invasive strategies to decipher the fetal genome, the placental transcriptome and the placental methylome. These data have far-reaching implications that would stimulate many further studies.


The fruits of this research project have led to a worldwide transformation of how prenatal testing is conducted.