Noninvasive Prenatal Detection of Fetal Trisomy 18 by Epigenetic Allelic Ratio Analysis in Maternal Plasma: Theoretical and Empirical Considerations

Yu, Tong; Ding, Chunming; Chiu, Rossa W.̉K.; Gerovassili, Ageliki; Chim, Stephen S.C.; Leung, Tak Yeung; Leung, Tse Ngong; Lau, Tze Kin; Nicolaides, Kypros H.; Lo, Y.M. Dennis

doi:10.1373/clinchem.2006.076851

Cited by 146 publications

(134 citation statements)

References 27 publications

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“…Apart from placental-specific mRNA transcripts, other types of fetal-specific nucleic acid species in maternal plasma could be used. One example is fetal epigenetic markers (12,21) which have recently been used for the noninvasive prenatal detection of trisomy 18 via the epigenetic allelic ratio (EAR) approach (10). Thus, we predict that digital EAR would be a possible analytical technique.…”

Section: Discussionmentioning

confidence: 99%

“…Second, fetal nucleic acids circulate in maternal plasma in a cell-free form, making it difficult to derive chromosome dosage information. Significant developments have recently been made (9)(10)(11). One approach focuses on the detection of nucleic acid species that are fetal-specific, including DNA fragments with a placenta-specific DNA methylation pattern (10,12) and RNA molecules expressed by the placenta (9).…”

mentioning

confidence: 99%

“…Significant developments have recently been made (9)(10)(11). One approach focuses on the detection of nucleic acid species that are fetal-specific, including DNA fragments with a placenta-specific DNA methylation pattern (10,12) and RNA molecules expressed by the placenta (9). Because circulating fetal nucleic acids are mainly derived from the placenta, the problem of maternal background interference can be overcome by targeting such molecules in maternal plasma (4).…”

mentioning

confidence: 99%

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Digital PCR for the molecular detection of fetal chromosomal aneuploidy

Lun²,

Chan³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

391

328

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Trisomy 21 is the most common reason that women opt for prenatal diagnosis. Conventional prenatal diagnostic methods involve the sampling of fetal materials by invasive procedures such as amniocentesis. Screening by ultrasonography and biochemical markers have been used to risk-stratify pregnant women before definitive invasive diagnostic procedures. However, these screening methods generally target epiphenomena, such as nuchal translucency, associated with trisomy 21. It would be ideal if noninvasive genetic methods were available for the direct detection of the core pathology of trisomy 21. Here we outline an approach using digital PCR for the noninvasive detection of fetal trisomy 21 by analysis of fetal nucleic acids in maternal plasma. First, we demonstrate the use of digital PCR to determine the allelic imbalance of a SNP on PLAC4 mRNA, a placenta-expressed transcript on chromosome 21, in the maternal plasma of women bearing trisomy 21 fetuses. We named this the digital RNA SNP strategy. Second, we developed a nonpolymorphism-based method for the noninvasive prenatal detection of trisomy 21. We named this the digital relative chromosome dosage (RCD) method. Digital RCD involves the direct assessment of whether the total copy number of chromosome 21 in a sample containing fetal DNA is overrepresented with respect to a reference chromosome. Even without elaborate instrumentation, digital RCD allows the detection of trisomy 21 in samples containing 25% fetal DNA. We applied the sequential probability ratio test to interpret the digital PCR data. Computer simulation and empirical validation confirmed the high accuracy of the disease classification algorithm.circulating fetal nucleic acids ͉ noninvasive prenatal diagnosis ͉ sequential probability ratio test ͉ trisomy 21 ͉ RNA SNP

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Digital PCR for the molecular detection of fetal chromosomal aneuploidy

Lun²,

Chan³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

391

328

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“…Recently, a number of approaches have been developed. One strategy targets a fetal-specific subset of nucleic acids in maternal plasma, e.g., placental mRNA (9)(10)(11) and DNA molecules bearing a placental-specific DNA methylation signature (12)(13)(14). The fetal chromosomal dosage is then assessed by allelic ratio analysis of SNPs within the targeted molecules.…”

Section: Down Syndrome ͉ Solexa Sequencing ͉ Trisomy 21mentioning

confidence: 99%

“…The fetal chromosomal dosage is then assessed by allelic ratio analysis of SNPs within the targeted molecules. These strategies are called the RNA-SNP allelic ratio approach (11) and the epigenetic allelic ratio approach (14). These allelic ratio-based methods can be used only for fetuses heterozygous for the analyzed SNPs.…”

Section: Down Syndrome ͉ Solexa Sequencing ͉ Trisomy 21mentioning

confidence: 99%

Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma

Chiu

Chan

Gao

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

841

758

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Chromosomal aneuploidy is the major reason why couples opt for prenatal diagnosis. Current methods for definitive diagnosis rely on invasive procedures, such as chorionic villus sampling and amniocentesis, and are associated with a risk of fetal miscarriage. Fetal DNA has been found in maternal plasma but exists as a minor fraction among a high background of maternal DNA. Hence, quantitative perturbations caused by an aneuploid chromosome in the fetal genome to the overall representation of sequences from that chromosome in maternal plasma would be small. Even with highly precise single molecule counting methods such as digital PCR, a large number of DNA molecules and hence maternal plasma volume would need to be analyzed to achieve the necessary analytical precision. Here we reasoned that instead of using approaches that target specific gene loci, the use of a locus-independent method would greatly increase the number of target molecules from the aneuploid chromosome that could be analyzed within the same fixed volume of plasma. Hence, we used massively parallel genomic sequencing to quantify maternal plasma DNA sequences for the noninvasive prenatal detection of fetal trisomy 21. Twenty-eight first and second trimester maternal plasma samples were tested. All 14 trisomy 21 fetuses and 14 euploid fetuses were correctly identified. Massively parallel plasma DNA sequencing represents a new approach that is potentially applicable to all pregnancies for the noninvasive prenatal diagnosis of fetal chromosomal aneuploidies.Down syndrome ͉ Solexa sequencing ͉ trisomy 21

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DNA Methylation Analysis by MALDI Mass Spectrometry

Tost

Gut

2012

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Noninvasive Prenatal Detection of Fetal Trisomy 18 by Epigenetic Allelic Ratio Analysis in Maternal Plasma: Theoretical and Empirical Considerations

Cited by 146 publications

References 27 publications

Digital PCR for the molecular detection of fetal chromosomal aneuploidy

Digital PCR for the molecular detection of fetal chromosomal aneuploidy

Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma

DNA Methylation Analysis by MALDI Mass Spectrometry

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