N I P T

: non-invasive prenatal diagnosis

To be able to offer prenatal diagnostic tests that have no risk to the pregnancy, investigators have tried to isolate fetal cells from the maternal serum. Although this is now technically possible, the snTalI number of cells actually present within maternal serum has prevented this technique from being developed to a clinically useful level.

In 1997, Lo etal." identified that portions of fetal DNA, released from the placental syncytiotrophoblast. were present in reasonable quantities within the maternal serum. These cell-tree fetal DNA segments are substantially smaller in size than maternal DNA and are therelore distinguishable." They are present in all pregnant women from early in the first trimester and they are cleared from maternal serum within a week of delivery. Their presence in maternal serum opened a new door of opportunity for clinically effective non-invasive prenatal diagnosis.

Owing to the relatively small quantities of fetal DNA in the maternal circulation (approximately 5% of total DNA), it has proved difficult to isolate pure extracts of fetal DNA. Instead, prenatal diagnosis has focused on identifying paternally inherited genes Within the DNA pool that will not be present in maternal DNA, such as pffA from the Y chromosome or DNA from the^RHD gene in a mother who is rhesus negative. As such, non-invasive prenatal diagnosis is frequently one of exclusion (the absence of Y chromosome material implies that the fetus is female) and can iherefore'only be used conlidently in weii-ueitned areas; namely, sex- determination, RhD and other blood group genotyping and specific single­gene disorders, such as 3-thalassaemia.

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POTENTIAL PROBLEMS

While these developments have proved very promising, there are a few cautionary points to note. Even within the parameters mentioned, no large studies have demonstrated 100% sensitivity and specificity. Parents need to be fully counselled and made aware of the potential pitfalls of a false-negative result. The studies themselves have looked at largely 'at risk' populations and need to be replicated within the general population. In addition, there are ethical dilemmas that need to be addressed: sex determination with a view lo sex-selection may be requested for non­medical indications and, with huge commercial input to these develop­ments, there may well be economic pressure from companies to make these tests readily available to the consumer. Currently, there is no formal legislation that covers non-invasive prenatal diagnosis.

FINALLY

The major challenge for those pioneering non-invasive prenatal diagnosis
is the detection of fetal aneuploidy. If this proved possible, the majority of invasive prenatal diagnostic tests could be avoided.

To detect aneuploidy, a technique to identify trisomic fetal material needs to be identified. Previous techniques that identify paternally inherited genetic material cannot be used in this situation, so a novel approach is required. The recent discovery of fetal mRNA in maternal serum mav prove to he a critical element in this process. If mRNA that is unique to fetal tissue, such as the placenta, can be isolated and the origins of the DNA can be localised to a specific gene (for example, on chromosome 21 or 18 or 13), there is the possibility of determining gene dosage in the fetus and establishing or excluding aneuploidy.

The most promising placental candidate that lu'N bPeit isolated to date is PLAC4 (placenta specific 4) which is located on chromosome 21. While PLAC4 is specific to the fetus and its locus is well-defined, there are still technical difficulties in accurately determining the chromosome dosage represented. However, given the huge commercial backing to this technology, it is likely that a solution will be found in the near future.

Conclusion

Given the rapidly changing face of prenatal diagnosis, it is important that those involved in antenatal care are conversant with the full spectrum of prenatal testing available to ensure that parents are reliably informed of the most appropriate options available to them, including the risks and limitations of each technique. Any invasive procedures performed should be executed with technical competence and minimal risk to the pregnancy. We await the results of continuing research in non-invasive prenatal diagnosis techniques to further refine the shape of prenatal testing offered on a population-wide basis in the next decade.

References

Royal College of Obstetricians and Gynaecologists. Amniocentesis. Green-top Guideline No. 8. London: RCOG; 2005 [www.rcog.org.uk/womens-health/ clinical-guidance/amniocentesis-and-chorionic-villus-sampling-green-top-8].