For the first time, a fetus has had its entire genome mapped from a sample of its mother鈥檚 blood. This technical tour de force could open the door to new methods of prenatal genetic diagnosis.
In 1997, researchers led by of the Chinese University of Hong Kong showed that 鈥渇loating鈥� fetal DNA can be detected in maternal blood plasma 鈥� it passes across the placenta from fetal cells that have broken down.
Lo鈥檚 discovery sparked a lot of interest, because it raised the possibility of diagnosing genetic problems in a fetus without the need for invasive procedures such as (CVS) or to extract fetal cells, both of which carry a small risk of inducing a miscarriage.
Advertisement
But it鈥檚 hard to distinguish fetal sequences from the larger quantity of a woman鈥檚 own DNA. This has so far largely limited practical applications of the technique to unambiguous situations in which particular fetal genes are not carried by the mother. For instance, fetal sex can be determined by detecting sequences from the male Y chromosome. It鈥檚 also possible to identify fetuses at risk of , where the mother鈥檚 immune system attacks a protein on her fetus鈥檚 red blood cells, by in the blood of women who are rhesus negative.
Lo has previously worked on methods to detect fetuses with Down鈥檚 syndrome from floating fetal DNA. Now, through a combination of brute-force DNA sequencing and sophisticated bioinformatics, his team has shown that it should be possible to detect any genetic disease from a sample of a pregnant woman鈥檚 blood.
Match and contrast
Lo recruited a couple who were at risk of having a child with , an inherited form of anaemia. By comparing the father鈥檚 genome and fetal DNA extracted by CVS with billions of fragments of DNA from the woman鈥檚 blood, Lo was able to construct maps of the entire fetal and maternal genomes. This revealed that the fetus was a carrier of beta-thalassaemia, but was not itself afflicted by the condition.
Of course, the whole point of sampling maternal blood is to avoid performing CVS or amniocentesis. But Lo says that this was just a proof of principle 鈥� in practice it should be possible to distinguish fetal and maternal sequences by comparing the fragments obtained from the woman鈥檚 blood sample with DNA sequenced from her relatives.
Showing that the entire fetal genome is present in a pregnant woman鈥檚 blood is an important development, says , a specialist in prenatal genetic diagnosis at Tufts University in Boston. 鈥淭his paper is beautiful,鈥� she says.
However, at present the analysis is too cumbersome and expensive for clinical use. 鈥淎t this moment, it would probably cost $200,000 per case,鈥� says Lo. 鈥淐utting costs will be very important.鈥�
While sampling the entire fetal genome for genetic defects may remain prohibitively expensive for some while, Lo hopes within a year to develop a test focused on about five important genetic conditions, with the sequencing costing around $2000.
Still, Bianchi believes that the bioinformatics involved in reliably distinguishing fetal from maternal DNA sequences from a blood sample may prove impractical for many clinical labs. She also points out that the latest estimates put the risk of miscarriage associated with amniocentesis . 鈥淎t some point, someone鈥檚 going to need to do an elegant cost-benefit analysis,鈥� she says.
Journal reference: , DOI: 10.1126/scitranslmed.3001720
