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Departments of
1
Chemical Pathology and
2
Obstetrics and Gynecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR
aAddress correspondence to this author at: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Room 38023, 1/F Clinical Sciences Building, 30-32 Ngan Shing St., Shatin, New Territories, Hong Kong SAR. Fax 852-2194-6171; e-mail loym{at}cuhk.edu.hk.
Background: Fetal DNA has been detected in maternal plasma by the use of genetic differences between mother and fetus. We explore the possibility of using epigenetic markers for the specific detection of fetal DNA in maternal plasma.
Methods: A differentially methylated region in the human IGF2-H19 locus and a single-nucleotide polymorphism in this region were chosen for the study. The methylation status in this region is maintained in such a way that the paternal allele is methylated and the maternal allele is unmethylated. The single-nucleotide polymorphism was typed by direct sequencing of PCR products. The methylation status of this region was ascertained by bisulfite conversion and methylation-specific PCR. Differentially methylated fetal alleles were detected in maternal plasma by direct sequencing and a primer-extension assay.
Results: Women in the second (n = 21; 17–21 weeks) and third (n = 18; 37–42 weeks) trimesters of pregnancy were recruited. Among these 39 volunteers, the 16 who were heterozygous for the single-nucleotide polymorphism were chosen for further analysis. In 11 of these 16 cases, paternally inherited methylated fetal alleles were different from the methylated alleles of the respective mothers. Using direct sequencing, we detected paternally inherited methylated fetal DNA in 6 of 11 (55%) cases. In 8 of the 16 heterozygous cases, the fetuses possessed an unmethylated maternally inherited allele that was different from the unmethylated allele of the mother. Using a primer-extension assay, we detected fetal-derived maternally inherited alleles in maternal plasma of four of eight (50%) cases.
Conclusions: These results represent the first use of fetal epigenetic markers in noninvasive prenatal analysis. These data may also have implications for the investigation of other types of chimerism.
The following articles in journals at HighWire Press have cited this article:
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  C. F Wright and L. S Chitty Cell-free fetal DNA and RNA in maternal blood: implications for safer antenatal testing BMJ, July 6, 2009; 339(jul06_2): b2451 - b2451. [Full Text]
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 E. A. Papageorgiou, H. Fiegler, V. Rakyan, S. Beck, M. Hulten, K. Lamnissou, N. P. Carter, and P. C. Patsalis Sites of Differential DNA Methylation between Placenta and Peripheral Blood: Molecular Markers for Noninvasive Prenatal Diagnosis of Aneuploidies Am. J. Pathol., May 1, 2009; 174(5): 1609 - 1618. [Abstract] [Full Text] [PDF]
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 E C W Hung, R W K Chiu, and Y M D Lo Detection of circulating fetal nucleic acids: a review of methods and applications J. Clin. Pathol., April 1, 2009; 62(4): 308 - 313. [Abstract] [Full Text] [PDF]
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 Y.M. D. Lo and R. W.K. Chiu Next-Generation Sequencing of Plasma/Serum DNA: An Emerging Research and Molecular Diagnostic Tool Clin. Chem., April 1, 2009; 55(4): 607 - 608. [Full Text] [PDF]
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 C. F. Wright and H. Burton The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis Hum. Reprod. Update, January 1, 2009; 15(1): 139 - 151. [Abstract] [Full Text] [PDF]
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C. B. M. Oudejans Noncoding RNA and DNA as Biomarkers: Toward an Epigenetic Fetal Barcode for Use in Maternal Plasma Clin. Chem., March 1, 2008; 54(3): 456 - 457. [Full Text] [PDF]
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S. S.C. Chim, S. Jin, T. Y.H. Lee, F. M.F. Lun, W. S. Lee, L. Y.S. Chan, Y. Jin, N. Yang, Y. K. Tong, T. Y. Leung, et al. Systematic Search for Placental DNA-Methylation Markers on Chromosome 21: Toward a Maternal Plasma-Based Epigenetic Test for Fetal Trisomy 21 Clin. Chem., March 1, 2008; 54(3): 500 - 511. [Abstract] [Full Text] [PDF]
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Y. M. Dennis Lo and R. W. K. Chiu Noninvasive Prenatal Diagnosis of Fetal Chromosomal Aneuploidies by Maternal Plasma Nucleic Acid Analysis Clin. Chem., March 1, 2008; 54(3): 461 - 466. [Abstract] [Full Text] [PDF]
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 T. W. Plaia, R. Josephson, Y. Liu, X. Zeng, C. Ording, A. Toumadje, S. N. Brimble, E. S. Sherrer, E. W. Uhl, W. J. Freed, et al. Characterization of a New NIH-Registered Variant Human Embryonic Stem Cell Line, BG01V: A Tool for Human Embryonic Stem Cell Research Stem Cells, March 1, 2006; 24(3): 531 - 546. [Abstract] [Full Text] [PDF]
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 S. S. C. Chim, Y. K. Tong, R. W. K. Chiu, T. K. Lau, T. N. Leung, L. Y. S. Chan, C. B. M. Oudejans, C. Ding, and Y. M. D. Lo Detection of the placental epigenetic signature of the maspin gene in maternal plasma PNAS, October 11, 2005; 102(41): 14753 - 14758. [Abstract] [Full Text] [PDF]
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 C. Gonzalez-Gonzalez, M. Garcia-Hoyos, M. J. Trujillo-Tiebas, I. Lorda-Sanchez, M. R. de Alba, F. Infantes, J. Gallego, J. Diaz-Recasens, C. Ayuso, and C. Ramos Application of Fetal DNA Detection in Maternal Plasma: A Prenatal Diagnosis Unit Experience J. Histochem. Cytochem., March 1, 2005; 53(3): 307 - 314. [Abstract] [Full Text] [PDF]
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F. Z. Bischoff, D. E. Lewis, and J. L. Simpson Cell-free fetal DNA in maternal blood: kinetics, source and structure Hum. Reprod. Update, January 1, 2005; 11(1): 59 - 67. [Abstract] [Full Text] [PDF]
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H. M. Muller, L. Ivarsson, H. Schrocksnadel, H. Fiegl, A. Widschwendter, G. Goebel, S. Kilga-Nogler, H. Philadelphy, W. Gutter, C. Marth, et al. DNA Methylation Changes in Sera of Women in Early Pregnancy Are Similar to Those in Advanced Breast Cancer Patients Clin. Chem., June 1, 2004; 50(6): 1065 - 1068. [Full Text] [PDF]
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O. Samura, N. Miharu, M. Hyodo, H. Honda, Y. Ohashi, N. Honda, T. Hara, and K. Ohama Cell-free Fetal DNA in Maternal Circulation after Amniocentesis Clin. Chem., July 1, 2003; 49(7): 1193 - 1195. [Full Text] [PDF]
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 X. Y. Zhong, W. Holzgreve, and S. Hahn Cell-free fetal DNA in the maternal circulation does not stem from the transplacental passage of fetal erythroblasts Mol. Hum. Reprod., September 1, 2002; 8(9): 864 - 870. [Abstract] [Full Text] [PDF]
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