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Prenatal diagnosis is an important part of obstetrics care. In the current prenatal programmes, definitive diagnosis of fetal genetic or chromosomal conditions is conducted through fetal sampling by amniocentesis or chorionic villus sampling. To obviate the risks of fetal miscarriage that are associated with the invasive sampling procedures, we have been developing non-invasive prenatal diagnostic tests based on cell-free fetal DNA analysis from maternal plasma. To date, fetal sex and rhesus D status determination by circulating fetal DNA analysis is performed clinically in many centres. Strategies for the non-invasive diagnosis of monogenic diseases have been developed. Accurate detection of fetal trisomy 21 by next-generation sequencing has been achieved. Many of the non-invasive prenatal tests could be introduced to the clinics as soon as cost-effective and high throughput protocols are developed., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Analysis of cell free fetal DNA (cffDNA) in maternal plasma provides the opportunity for reliable, timely, safe and cost-effective diagnosis of single gene disorders. The detection of certain fetal loci using cffDNA and conventional molecular analytic approaches is possible from 4 weeks gestation. To date, non-invasive first-trimester analysis for single gene disorders has been limited by assay sensitivity and specificity, due to the background maternal DNA. The anticipated ability to enrich the fetal component of cell free DNA will increase the robustness of tests and permit semi-quantitative analysis, broadening the scope of testing to include recessive disorders such as cystic fibrosis. Testing for large-scale mutations might remain limited by the fragmented nature of cffDNA and, when testing very early in gestation, careful ultrasound examination will be needed to determine the number of gestational sacs, because of the risk of discordant twin pregnancies.

Prenatal fetal sex determination is undertaken in women at high risk of serious genetic disorders affecting a specific sex. Traditionally, this is undertaken by invasive testing, usually chorionic villus sampling, which carries a risk of miscarriage of around 1%. The identification of cell-free fetal DNA in the maternal circulation has allowed the development of 'non-invasive prenatal diagnostic tests', which permit fetal sex determination without risk to the pregnancy.

Although the first finding that fetal cells can enter the maternal circulation was made more than a century ago, it is still unclear if this finding will be translated into a clinically useful diagnostic tool in the foreseeable future. However, significant progress has been made via the analysis of cell-free fetal DNA in maternal plasma/serum and clinical services are now already being offered for the determination of fetal rhesus D status and sex. Currently, however, this technology is really only suited for the analysis of fetal genetic loci completely absent from the maternal genome. The detection of more subtle fetal genetic traits, such as point mutations involved in Mendelian disorders (thalassaemia, cystic fibrosis), is considerably more complex. Preliminary reports indicate that the detection of fetal aneuploidies might be possible using epigenetically modified genes, e.g. maspin on chromosome 18. Additionally, an exiting recent development is that it might be feasible to detect Down syndrome via the quantitative assessment of placentally derived cell-free mRNA of chromosome-21-specific genes such as PLAC4.