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Received on October 10, 2007
Accepted on November 20, 2007
Molecular Diagnostics and Genetics |
1 Centre for Research into Circulating Fetal Nucleic Acids, Li Ka Shing Institute of Health Sciences, and Department of Obstetrics and Gynaecology
2 Centre for Research into Circulating Fetal Nucleic Acids, Li Ka Shing Institute of Health Sciences, and Department of Chemical Pathology
3 Centre for Research into Circulating Fetal Nucleic Acids, Li Ka Shing Institute of Health Sciences, and Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR
4 Department of Obstetrics and Gynaecology Hong Kong SAR
* To whom correspondence should be addressed. E-mail: loym{at}cuhk.edu.hk.
BACKGROUND: The presence of fetal DNA in maternal plasma represents an opportunity to use fetal genetic material for noninvasive prenatal diagnosis; however, the coexisting background maternal DNA complicates the analysis of aneuploidy in such fetal DNA. Recently, the SERPINB5 gene on chromosome 18 was shown to exhibit different DNA-methylation patterns in the placenta and maternal blood cells, and the allelic ratio for placenta-derived hypomethylated SERPINB5 in maternal plasma was further shown to be useful for noninvasive detection of fetal trisomy 18.
METHODS: To develop a similar method for the noninvasive detection of trisomy 21, we used methylation-sensitive single nucleotide primer extension and/or bisulfite sequencing to systematically search 114 CpG islands (CGIs)—76% of the 149 CGIs on chromosome 21 identified by bioinformatic criteria—for differentially methylated DNA patterns. The methylation index (MI) of a CpG site was estimated as the proportion of molecules methylated at that site.
RESULTS: We identified 22 CGIs in which CpG sites that were either completely unmethylated (MI = 0.00) in maternal blood cells and methylated in the placenta (MI range, 0.22–0.65), or completely methylated (MI = 1.00) in maternal blood cells and hypomethylated in the placenta (MI range, 0.00–0.75). We detected, for the first time, placental DNA- methylation patterns on chromosome 21 in maternal plasma during pregnancy and observed their postpartum clearance.
CONCLUSION: Twenty-two (19%) of the 114 studied CGIs on chromosome 21 showed epigenetic differences between samples of placenta and maternal blood cells; these CGIs may provide a rich source of markers for noninvasive prenatal diagnosis.
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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 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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 J. Beck, H. B. Urnovitz, J. Riggert, M. Clerici, and E. Schutz Profile of the Circulating DNA in Apparently Healthy Individuals Clin. Chem., April 1, 2009; 55(4): 730 - 738. [Abstract] [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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 R. W. K. Chiu, K. C. A. Chan, Y. Gao, V. Y. M. Lau, W. Zheng, T. Y. Leung, C. H. F. Foo, B. Xie, N. B. Y. Tsui, F. M. F. Lun, et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma PNAS, December 23, 2008; 105(51): 20458 - 20463. [Abstract] [Full Text] [PDF]
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F. M. F. Lun, N. B. Y. Tsui, K. C. A. Chan, T. Y. Leung, T. K. Lau, P. Charoenkwan, K. C. K. Chow, W. Y. W. Lo, C. Wanapirak, T. Sanguansermsri, et al. Noninvasive prenatal diagnosis of monogenic diseases by digital size selection and relative mutation dosage on DNA in maternal plasma PNAS, December 16, 2008; 105(50): 19920 - 19925. [Abstract] [Full Text] [PDF]
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 J. F. Smith and Y. Blumenfeld Cell-free Fetal DNA in Maternal Plasma: Progress and Potential NeoReviews, August 1, 2008; 9(8): e332 - e337. [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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