Editors' ChoiceDown’s Syndrome

Fetal DNA: A Needle in the Haystack

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Science Translational Medicine  30 Mar 2011:
Vol. 3, Issue 76, pp. 76ec43
DOI: 10.1126/scitranslmed.3002425

The previous discovery of circulating free fetal DNA in maternal blood during pregnancy has opened a door for the development of noninvasive prenatal genetic screening techniques. However, the amount of free fetal DNA that can be identified in a peripheral blood sample is miniscule (3 to 6% of circulating free DNA), and finding it among this excess of maternal DNA is akin to finding a needle in the proverbial haystack. A major limitation has been the ability to both enrich a peripheral blood sample for fetal DNA and accurately discriminate between maternal and fetal cells. Interestingly, fetal cells appear to have a unique epigenetic footprint—meaning, the DNA has specific methylation (–CH3) patterns—which could make discrimination easier between mother and fetus. Now, Papageorgiou and colleagues have used these methylation differences to reliably diagnose trisomy 21, the genetic basis of Down’s syndrome.

The authors first identified a specific pattern of differentially methylated regions on the fetal chromosome 21 that predicted either a normal or trisomy 21 pregnancy. Using a technique termed methylated DNA precipitation (MeDiP), they next added an antibody to maternal blood samples that specifically recognizes methylated regions on a gene promoter and analyzed these differences using quantitative polymerase chain reaction (PCR). This approach provided the necessary one-two punch of discrimination and enrichment, leading to the correct identification of 14 Down’s syndrome cases and 26 normal cases in a blind sampling of 40 pregnant women.

Noninvasive prenatal diagnostic techniques such as this might soon obviate the need for more invasive procedures, including amniocentesis (extraction of amniotic fluid) and sampling of chorionic villi. For many women, these traditional methods harbor an unacceptably high risk of miscarriage. Continued refinement is needed for large-scale application, however, and the method applied here might not be suitable to screen for every genetic disorder. For instance, in order for MeDiP to work, the fetal gene of interest must be hypermethylated in comparison to the maternal gene. Still, Papageorgiou et al. are moving forward to develop similar methods that can be used to detect aneuploidies of chromosomes 13, 18, X, and Y, thereby expanding prenatal diagnostic options for expectant moms.

E. A. Papageorgiou et al., Fetal-specific DNA methylation ratio permits noninvasive prenatal diagnosis of trisomy 21. Nat. Med. 6 March 2011 (10.1038/nm.2312). [Abstract]

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