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Will Epigenetic Allelic Ratio Analysis Turn Prenatal Diagnosis of Trisomy 18 on Its EAR?

Division of Genetics, Departments of Pediatrics and, Obstetrics and Gynecology, Tufts-New England Medical Center, 750 Washington St, Box 394, Boston, MA 02111, Fax: 617-636-1469, E-mail DBianchi@tufts-nemc.org

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In a proof of principle report elsewhere in this issue of Clinical Chemistry, Tong et al. (1) describe a novel approach to the noninvasive prenatal diagnosis of a human chromosomal abnormality by analyzing the allelic ratio of a polymorphism present within the methylated promoter of a DNA sequence on chromosome 18q21.3, maspin (SERPINB5). This method differs from other approaches to noninvasive diagnosis of aneuploidy in that it is truly diagnostic, as opposed to being a screen.

The technique described in this paper relies first on the isolation of cell-free fetal DNA from maternal plasma, and second, on the fact that there is differential methylation of maspin. In a previous report from the same laboratory group (2) maspin was shown to be hypomethylated (i.e., actively expressed) in placenta and hypermethylated (i.e., silenced) in maternal leukocytes, which are the source of most circulating cell-free DNA in plasma (3). By the method of bisulfite modification, unmethylated cytosine residues in the DNA sequence are converted to uracil, but methylated cytosine residues remain unchanged. This sequence difference is then exploited via methylation-specific PCR amplification, followed by allele-specific primer extension. A single-base variation [or single nucleotide polymorphism (SNP)] within the promoter sequence is then used as a focus for mass spectrometric analysis, with subsequent analysis of the ratio of copy numbers of the particular DNA sequence variation.

In the present study, the U-maspin-156 SNP was used. A normal euploid fetus might be genotyped as AC at this locus. Fetuses with trisomy 18, if polymorphic, would be genotyped as having AAC or ACC. By measuring the ratio of . . . [Full Text of this Article]