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Received on July 19, 2006
Accepted on September 19, 2006
Molecular Diagnostics and Genetics |
1 Department of Chemical Pathology, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
2 Centre for Emerging Infectious Diseases and Li Ka Shing Instituet of Health Sciences, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
3 Department of Chemical Pathology and Li Ka Shing Instituet of Health Sciences, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
4 Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, United Kingdom
5 Department of Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
* To whom correspondence should be addressed. E-mail: loym{at}cuhk.edu.hk.
Background: The discovery of cell-free fetal DNA in maternal plasma has opened up new possibilities for noninvasive prenatal diagnosis. However, the use of maternal plasma fetal DNA for the direct detection of fetal chromosomal aneuploidies has not been reported. We postulate that the aneuploidy status of a fetus could be revealed by an epigenetic allelic ratio approach, i.e., by analyzing the allelic ratio of a single-base variation present within DNA molecules exhibiting a placental-specific epigenetic signature in maternal plasma.
Methods: Placental-derived fetal-specific unmethylated maspin promoter sequences on human chromosome 18 were detectable in placental-maternal DNA mixtures and in maternal plasma by bisulfite modification followed by methylation-specific PCR (MSP) and primer extension. The ratios between the extension products of the 2 alleles were calculated for heterozygous placentas, placental-maternal blood cell DNA mixtures, and maternal plasma samples. The allelic ratios were compared between pregnancies carrying trisomy 18 and euploid fetuses.
Results: The epigenetic allelic ratios of all tested trisomy 18 samples deviated from the reference range obtained from euploid samples (placental DNA, 1.135 to 2.052; placental-maternal DNA mixtures, 1.170 to 1.985; maternal plasma, 0.330 to 3.044; without skew correction on the raw mass spectrometric data). A theoretical model was established and validated that predicted that a minimum of 200 copies of genomic DNA after bisulfite conversion were required for distinguishing euploid and aneuploid fetuses with confidence.
Conclusion: Epigenetic allelic ratio analysis of maternal plasma DNA represents a promising approach for noninvasive prenatal diagnosis of fetal chromosomal aneuploidies.
The following articles in journals at HighWire Press have cited this article:
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  T. Chu, K. Bunce, W. A. Hogge, and D. G. Peters Statistical model for whole genome sequencing and its application to minimally invasive diagnosis of fetal genetic disease Bioinformatics, May 15, 2009; 25(10): 1244 - 1250. [Abstract] [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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Y. K. Tong, R. W.K. Chiu, T. Y. Leung, C. Ding, T. K. Lau, T. N. Leung, and Y.M. D. Lo Detection of Restriction Enzyme Digested Target DNA by PCR Amplification Using a Stem-Loop Primer: Application to the Detection of Hypomethylated Fetal DNA in Maternal Plasma Clin. Chem., November 1, 2007; 53(11): 1906 - 1914. [Abstract] [Full Text] [PDF]
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R. W. Y. Chan, C. A. Graham, T. H. Rainer, N. Y. L. Lam, R. W. K. Chiu, K.-W. Chik, V. Lee, and Y. M. D. Lo Use of a Bone Marrow Transplantation Model System to Demonstrate the Hematopoietic Origin of Plasma S100B mRNA Clin. Chem., October 1, 2007; 53(10): 1874 - 1876. [Full Text] [PDF]
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Y. M. D. Lo, F. M. F. Lun, K. C. A. Chan, N. B. Y. Tsui, K. C. Chong, T. K. Lau, T. Y. Leung, B. C. Y. Zee, C. R. Cantor, and R. W. K. Chiu From the Cover: Digital PCR for the molecular detection of fetal chromosomal aneuploidy PNAS, August 7, 2007; 104(32): 13116 - 13121. [Abstract] [Full Text] [PDF]
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D. W. Bianchi Will Epigenetic Allelic Ratio Analysis Turn Prenatal Diagnosis of Trisomy 18 on Its EAR? Clin. Chem., December 1, 2006; 52(12): 2182 - 2183. [Full Text] [PDF]
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