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DOI: 10.1369/jhc.4R6362.2005
Volume 53 (3): 293-296, 2005
Copyright ©The Histochemical Society, Inc.
REVIEW |
Recent Advances in Fetal Nucleic Acids in Maternal Plasma
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong
Correspondence to: Y.M. Dennis Lo, Dept. of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region, China. E-mail: loym{at}cuhk.edu.hk
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Summary |
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 Top Summary IntroductionDiagnostic ApplicationsQuantitative AberrationsFetal RNA in Maternal...Characterization of Fetal...Analytical AspectsConclusionsLiterature Cited |
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The discovery of cell-free fetal DNA in maternal plasma in 1997 has opened up new possibilities for noninvasive prenatal diagnosis. Circulating fetal DNA molecules have been detected in maternal plasma from the first trimester onwards and can be robustly detected using a variety of molecular methods. This approach has been used for the prenatal investigation of sex-linked diseases, fetal RhD status, and prenatal exclusion of ß-thalassemia major. Recently, fetal RNA has also been found in maternal plasma. Such fetal RNA has been shown to originate from the placenta and to be remarkably stable. The use of microarray-based approaches has made it feasible to rapidly generate new circulating RNA markers. It is hoped that further developments in this field will make the routine and widespread practice of noninvasive nucleic acid–based prenatal diagnosis for common pregnancy-associated disorders feasible in the near future.
(J Histochem Cytochem 53:293–296, 2005)
Key Words: noninvasive prenatal diagnosis • plasma DNA • plasma RNA
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Introduction |
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TopSummaryIntroductionDiagnostic ApplicationsQuantitative AberrationsFetal RNA in Maternal...Characterization of Fetal...Analytical AspectsConclusionsLiterature Cited |
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PRENATAL DIAGNOSIS is now part of established obstetric practice in many countries. However, conventional methods of obtaining fetal tissues for genetic analysis, including amniocentesis and chorionic villus sampling, are invasive and constitute a finite risk to the unborn fetus. It has been a long-sought goal in human genetics to develop methods of obtaining fetal genetic materials for analysis. One approach that has been extensively investigated over the past few decades is the isolation of fetal cells from maternal blood (Walknowska et al. 1969
; Schroder 1975; Herzenberg et al. 1979; Lo et al. 1989; Bianchi et al. 1990). However, the rarity of such circulating fetal cells has limited the development and practical use of this approach (Bianchi et al. 2002).
In 1997, Lo et al. discovered that cell-free fetal DNA is present in the plasma and serum of pregnant women (Lo et al. 1997). Fetal DNA is present in maternal plasma from the first trimester onwards, with concentrations that increase with progressing gestational age (Lo et al. 1998b). After delivery, fetal DNA is cleared very rapidly from the maternal plasma (Lo et al. 1999d). Fetal DNA is present in maternal plasma in a much higher fractional concentration than fetal DNA in the cellular fraction of maternal blood (Lo et al. 1998b). This important feature has made the robust detection of fetal DNA possible, even without special enrichment procedures.
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Diagnostic Applications |
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TopSummaryIntroductionDiagnostic ApplicationsQuantitative AberrationsFetal RNA in Maternal...Characterization of Fetal...Analytical AspectsConclusionsLiterature Cited |
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The first marker that was developed for fetal DNA detection in maternal plasma was the Y chromosome, which is present in male fetuses (Lo et al. 1997
,1998b). The robustness of Y chromosomal markers has been reproduced by many workers in the field (Costa et al. 2001; Sekizawa et al. 2001a). This approach constitutes a highly accurate method for the determination of fetal gender, which is useful for the prenatal investigation of sex-linked diseases (Costa et al. 2002).
Maternal plasma DNA analysis is also useful for the noninvasive prenatal determination of fetal RhD blood group status in RhD-negative pregnant women (Faas et al. 1998; Lo et al. 1998a). This approach has been shown by many groups to be highly accurate (Zhong et al. 2000b), and has been introduced as a routine service by the British National Blood Service since 2001 (Finning et al. 2002). The latter development is important because this is the first routine use of noninvasive DNA-based prenatal diagnosis.
More recently, maternal plasma DNA analysis has been shown to be useful for the noninvasive prenatal exclusion of fetal ß-thalassemia major (Chiu et al. 2002b). A similar approach has also been used for prenatal detection of the HbE gene (Fucharoen et al. 2003).
Other genetic applications of fetal DNA in maternal plasma include the detection of achondroplasia (Saito et al. 2000), myotonic dystrophy (Amicucci et al. 2000), cystic fibrosis (Gonzalez-Gonzalez et al. 2002), Huntington disease (Gonzalez-Gonzalez et al. 2003), and congenital adrenal hyperplasia (Rijnders et al. 2001; Chiu et al. 2002a). It is expected that the spectrum of such applications will increase over the next few years.
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Quantitative Aberrations |
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TopSummaryIntroductionDiagnostic ApplicationsQuantitative AberrationsFetal RNA in Maternal...Characterization of Fetal...Analytical AspectsConclusionsLiterature Cited |
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Shortly after the documentation of the concentrations of circulating fetal DNA in maternal plasma in normal pregnancies, investigators studied its possible quantitative aberrations in pathologies. The first disease that was associated with such quantitative aberrations of fetal DNA in maternal serum was preeclampsia (Lo et al. 1999c
), in which a fivefold elevation in the median circulating fetal DNA concentration was found. These results have now been reproduced by a number of other groups (Zhong et al. 2001; Swinkels et al. 2002). It has recently been shown that at least part of such elevation might be attributable to the impaired clearance of circulating fetal DNA in preeclamptic pregnancies (Lau et al. 2002). In addition, fetal DNA concentration has also been found to be elevated before the onset of preeclampsia (Leung et al. 2001; Zhong et al. 2002; Levine et al. 2004). In addition to preeclampsia, quantitative aberrations involving circulating fetal DNA have also been described in certain chromosomal aneuploidies (Lo et al. 1999b; Zhong et al. 2000a; Lee et al. 2002; Farina et al. 2003; Wataganara et al. 2003), preterm labor (Leung et al. 1998), hyperemesis gravidarum (Sekizawa et al. 2001b), and invasive placentation (Sekizawa et al. 2002). Taken together, these data suggest that it might be possible to use fetal DNA in maternal plasma or serum for predicting at-risk pregnancies. |
Fetal RNA in Maternal Plasma |
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TopSummaryIntroductionDiagnostic ApplicationsQuantitative AberrationsFetal RNA in Maternal...Characterization of Fetal...Analytical AspectsConclusionsLiterature Cited |
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Since the success with detecting plasma DNA, a number of investigators have turned their attention to plasma RNA. Detection of plasma DNA was first achieved through the detection of tumor-derived RNA in the plasma and serum of cancer patients (Kopreski et al. 1999
; Lo et al. 1999a). Poon et al. (2000) were the first to show that fetal RNA is present in the plasma of pregnant women, through the detection of mRNA from a gene that is expressed on the Y chromosome. The detection of cell-free RNA molecules in plasma is surprising, in view of the well-known instability of RNA molecules. Tsui et al. (2002) investigated this apparent paradox in detail and reported that endogenous plasma RNA molecules, in contrast to extracted and purified RNA, are highly stable. Ng et al. (2002) further showed that such endogenous plasma RNA molecules are associated with subcellular particles that might protect such RNA molecules from degradation (Hasselmann et al. 2001).
In search of a gender-independent fetal RNA marker that can be detected in maternal plasma, Ng et al. (2003b) recently showed that mRNA expressed by the placenta is readily detectable in maternal plasma. These authors initially used mRNA coding for human placental lactogen and the ß-subunit of human chorionic gonadotrophin as model systems and have shown that these mRNA species are easily detectable using real-time RT-PCR. Tsui et al. (2004) have recently shown that with the use of expression microarrays, it is possible to rapidly identify new mRNA species that are detectable in maternal plasma. Ng et al. (2003a) have further shown that maternal plasma RNA analysis can be used for the prenatal detection of certain pregnancy-associated disorders, including preeclampsia and certain chromosomal aneuploidies (Ng et al. 2004). Recently, placenta-derived chromosome 21–specific mRNA species (Oudejans et al. 2003) and fetus-derived hematopoietic mRNA species have also been detected in maternal plasma (Wataganara et al. 2004). It is expected that further plasma RNA markers will be developed over the next few years.
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Characterization of Fetal Nucleic Acids in Maternal Plasma |
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TopSummaryIntroductionDiagnostic ApplicationsQuantitative AberrationsFetal RNA in Maternal...Characterization of Fetal...Analytical AspectsConclusionsLiterature Cited |
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Most workers who have studied fetal nucleic acids in maternal plasma have focused on exploring the potential diagnostic applications. In comparison, there have been relatively few publications on the molecular characterization of such circulating DNA molecules. Chan et al. (2004)
have recently studied the size distribution of the DNA molecules in the plasma of pregnant women. These investigators found that the DNA molecules in the plasma of pregnant women are longer than those in nonpregnant subjects. In addition, they found that in the maternal plasma, fetal DNA molecules are generally shorter than maternal DNA molecules. Apart from their intrinsic biological interest, these data have also opened up the possibility of the enrichment of circulating fetal DNA molecules by size separation. These data have recently been independently confirmed (Li et al. 2004). In the future, it would be of interest to explore the potential variation in the size of circulating DNA molecules under various physiological and pathological conditions. |
Analytical Aspects |
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TopSummaryIntroductionDiagnostic ApplicationsQuantitative AberrationsFetal RNA in Maternal...Characterization of Fetal...Analytical AspectsConclusionsLiterature Cited |
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The demonstration of the presence of fetal nucleic acids in maternal plasma has created a flurry of activity in many laboratories in exploring new diagnostic applications for this noninvasive source of fetal nucleic acids. However, important differences have been noted in the techniques used by different laboratories. One of the earliest preanalytical factors that has been highlighted for detailed study is the speed of centrifugation used for plasma and serum separation (Chiu et al. 2001
; Lo and Poon 2003). Other important differences among laboratories include the use of different primer and probe sets (Lo et al. 1998b; Honda et al. 2001; Sekizawa et al. 2001a; Costa et al. 2002) and DNA extraction methods (Lo et al. 1997; Costa and Ernault 2002). Recently, Dhallan et al. (2004) reported that the addition of formaldehyde to the blood collection tubes may enhance the fractional fetal DNA concentration in a proportion of samples. If these results are reproducible, this would simplify certain applications of fetal DNA in maternal plasma. For the possible future routine of this technology, some form of standardization would be important. In this regard, it is encouraging to see that a number of laboratories are already collaborating to enhance the cross-laboratory comparability of the generated data (Johnson et al. 2004). |
Conclusions |
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TopSummaryIntroductionDiagnostic ApplicationsQuantitative AberrationsFetal RNA in Maternal...Characterization of Fetal...Analytical AspectsConclusionsLiterature Cited |
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The discovery of cell-free fetal DNA and RNA in maternal plasma has opened up new possibilities for noninvasive prenatal diagnosis. Over the past 7 years significant progress has been made in our understanding of the biology and diagnostic implications of fetal nucleic acids in maternal plasma. It is hoped that further developments over the next few years will enable us to move even closer to the goal of widespread use of noninvasive nucleic acid-based prenatal diagnosis.
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Acknowledgments |
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Supported in part by a Central Allocation Grant (CUHK1/03C) and an Earmarked Research Grant (CUHK4474/03M) from the Hong Kong Research Grants Council, and by a grant from the Innovation and Technology Fund (ITS/195/01).
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Footnotes |
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Presented in part at the 14th Workshop on Fetal Cells and Fetal DNA: Recent Progress in Molecular Genetic and Cytogenetic Investigations for Early Prenatal and Postnatal Diagnosis, Friedrich Schiller University, Jena, Germany, April 17–18, 2004.
Received for publication April 28, 2004; accepted June 3, 2004
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