Diagnosi fetale su sangue materno

By Jef Akst
Mom's blood carries fetus genome
A complete copy of the fetal genome exists in the mother's blood, suggesting many prenatal diagnoses could be performed noninvasively

[Published 8th December 2010 07:00 PM GMT]

Circulating in the blood of pregnant women is the full genome of their unborn child, according to a study published online today (December 8) in Science Translational Medicine.


Image: Wikimedia commons, Swangerschaft
The results suggest that whole genome sequencing of fetuses may be possible without invasive procedures, and hold implications for the prenatal diagnoses of every genetic disease.

This study provides "a window into the fetal genome," said reproductive geneticist Diana W. Bianchi of the Mother Infant Research Institute at the Tufts University School of Medicine, who was not involved in the research. "In principle, that means that you could noninvasively prenatally diagnose anything because the sequence is going to be there."

In 1997, chemical pathologist Dennis Lo of The Chinese University of Hong Kong and his colleagues discovered the presence of fetal DNA in maternal blood. Scientists have since developed noninvasive procedures to prenatally diagnose certain diseases. Down syndrome, for example, results from an abnormal number of chromosomes, and can be detected by searching mother's blood for disproportionate amounts of DNA from different chromosomes. And genetic diseases inherited from the father may also be detected by searching the mother's blood for the paternal mutation.

It was unclear, however, if the entire fetal genome was present in the maternal plasma, which would give clinicians more confidence in the tests currently available by limiting the rate of false-negative results. Additionally, it might make it possible to screen for genetic diseases that are caused by genetic mutations inherited from the mother, as well as sequence the entire genome of the unborn child, without subjecting the mother to invasive procedures that carry a small risk of miscarriage.

Current procedures for diagnosing such subtle genetic diseases, such as chorionic villus sampling (CVS) and amniocentesis, involve putting a catheter up through the woman's cervix or a needle through her belly, to collect fetal tissue, and pose a 1 percent risk of miscarriage.

Now, Lo's group has demonstrated that it really is all there -- in a low, but constant proportion to the maternal DNA. The team gathered the DNA from a couple visiting an obstetrics clinic for the CVS procedure that could prenatally diagnosis their baby with Β-thalassemia, a recessive blood disorder. Each parent was a carrier, giving the fetus a 25 percent chance of inheriting both mutations and developing the disease. With DNA from the mother, father, and fetus, Lo and his colleagues were able to demonstrate that the entire fetal genome was present in the mother's blood and construct a fetal genomic map that could be scanned for disease-causing mutations. Using this approach, the team determined that the baby had inherited the father's mutation, but not the mother's, and was thus a carrier for Β-thalassemia.

"This new technique has opened up the possibility that one can screen for multiple genetic disorders" without using invasive procedures, Lo told The Scientist in an email.

But it's not so easy, Bianchi warned. "Only about 10-11 percent of the total cell free DNA is fetal in origin," she said -- while CVS, which removes a small piece of placenta, retrieves only fetal tissue. In addition to being much more cost effective, "[these procedures] allow you to be highly accurate and diagnostic [because] you don't have to deal with the technical challenge of the fact that there's mixed genomes there."

In fact, to construct the fetal genomic map, Lo and his colleagues had to use genetic information about the mother and father. Furthermore, to decipher which DNA was of fetal origin, the group had to use the fetal DNA obtained from the CVS procedure the couple had gotten to diagnosis the baby's risk of Β-thalassemia, which would normally not be available for prenatal diagnoses attempting to avoid invasive procedures.

Plus, to separate the baby's DNA from the mother's, it's not enough to simply sequence the mother's nucleotide sequence. The researchers also have to know the maternal haplotype -- the genetic segments that are passed down to the child as cohesive units, which contain critical information about linked polymorphisms. Under normal clinical circumstances, this would require looking at the genetic information of other family members, or haplotype information about entire populations.

This adds additional cost -- perhaps around $1,500 to determine the maternal haplotype, Lo said -- to an already expensive procedure, which currently would cost some $200,000 per case. Lo and his team are currently working to develop more targeted tests, however, that focus in on disease-causing genes and could be 50 to 100 times cheaper, he said.

There's the also added complication of getting other people involved, Bianchi said. "You're getting that much farther away from the fetus," she said. "It's so much easier to look at pure fetal DNA, and make the diagnosis on the fetus." But this option, of course, holds that 1 percent risk of miscarriage.

Eventually what's needed is a risk-benefits analysis, Bianchi added. For parents, such as the couple in this study, who are both carriers for a particular disease and thus have a 25 percent risk of having an affected child, the miniscule risk of miscarriage may be worth the greater certainty that comes with the invasive procedures, she said. On the other hand, "if you were a 45 year old woman who had taken 5 years to conceive with IVF, any risk of a miscarriage is going to be intolerable."

The techniques developed in this study may also have implications beyond prenatal diagnoses, Lo said. "The approach described in our paper might also have [an] application in the analysis of other medically important species of DNA in plasma, e.g. tumor DNA in the plasma of cancer patients," which may aid in cancer diagnosis.

Y.M.D. Lo, "Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus," Science Trans Med, 2(61):61ra91, 2010.