A new study published in Nature last week reveals how researchers have for the first time developed a way to sequence the genome of an unborn baby using only a sample of blood from the mother. The researchers believe this brings fetal genetic testing one step closer to routine clinical use.
Senior author Dr Stephen Quake is the Lee Otterson Professor in the School of Engineering and professor of bioengineering and of applied physics at Stanford University in the US. He told the press:
“We’re interested in identifying conditions that can be treated before birth, or immediately after.”
“Without such diagnoses, newborns with treatable metabolic or immune system disorders suffer until their symptoms become noticeable and the causes determined,” said Quake, who is also co-chair of Stanford’s Department of Bioengineering.
The study follows one reported last month by the University of Washington, where researchers sequenced a fetal genome using a blood sample from the mother, plus DNA samples from the mother and the father.
However, fetal genome sequencing that uses only a blood sample from the mother offers a significant advantage when the biological father is unknown or is unwilling to provide a sample. As many as one in ten babies born in the US is of unknown paternity, according to a Stanford press statement on the research.
The ability to diagnose medical conditions in the womb is not new: for decades women have undergone amniocentesis or chorionic villus sampling to see if their fetus has any genetic abnormalities. These tests retrieve samples from the amniotic fluid or the fetus itself, using a needle inserted into the uterus. Such invasive procedures carry a risk in that one in every 200 or so will trigger a miscarriage. And the number of genetic conditions they can test for is limited.
The researchers believe fetal genetic testing will become increasingly common as the cost of the technology comes down.
Quake and colleagues showed that even just sequencing the exome, the 1% of the genome that codes the genes that are expressed to make a fetus, can give information that is clinically useful.
Dr Diana Bianchi is executive director of the Mother Infant Research Institute at Tufts Medical Center, and was not involved in the Nature study. She said:
“The problem of distinguishing the mother’s DNA from the fetus’s DNA, especially in the setting where they share the same abnormality, has seriously challenged investigators working in prenatal diagnosis for many years.”
In their study, using whole-genome and exome sequences, Quake and colleagues were able to determine that a fetus had DiGeorge syndrome, a condition associated with heart and neuromuscular problems, as well as cognitive impairment, that is caused by a short deletion of chromosome 22.
Symptoms and severity of DiGeorge syndrome can vary among affected individuals: some babies born with the condition can have heart defects and convulsions due to very low levels of calcium, and it can also cause significant problems with feeding.
Bianchi, who also chairs the clinical advisory board of Verinata Health Inc, Redwood City, a privately-held company that markets a fetal genetic test using technology developed by Quake, said:
“In this paper, Quake’s group elegantly shows how sequencing of the exome can show that a fetus has inherited DiGeorge syndrome from its mother.”
The method that Quake’s lab has developed relies on the fact that as well as carrying DNA from her own cells, the blood of a pregnant woman also carries DNA from fetal cells, and this amount goes up steadily during pregnancy, rising to as much as 30% of the total amount in the last part of the third trimester.
Four companies in the US currently market tests based on work done in Quake’s lab in 2008, where he and his team pioneered a method that uses relative levels of fetal DNA in the mother’s blood to diagnose conditions caused by missing or extra chromosomes, such as Down syndrome.
Two companies in particular are licensed by Stanford to use Quake’s 2008 approach, one is Verinata, the other is Fluidigm Inc in San Francisco. According to Stanford, neither was involved in this latest study, although Quake and one other researcher hold shares in the companies.
In this latest study, the team moves the 2008 method on a stage: the new approach recognizes that the fetal DNA in the mother’s bloodstream contains genetic material from both the mother and the father.
So, unlike the recent University of Washington study, Quake and colleagues were able to distinguish and isolate fetal DNA without having to take a sample from the father. They did this by process of elimination and comparing the relative levels of regions known as haplotypes, from maternal (from both mother and fetus) and paternal DNA.
A haplotype describes genetic material inherited from a single parent: either a pair of genes on one chromosome, or all of the genes on a chromosome that came from a single parent.
For this study, the team tested the method in two pregnancies: one where the mother had DiGeorge syndrome; the other where the mother did not. Through exome and whole-genome sequencing they showed that the fetus of the mother with DiGeorge syndrome had inherited the condition. This was confirmed by comparing the predicted sequencing with one obtained after birth from umbilical cord blood.
These tests were done retrospectively on anonymous samples. In a clinical setting, the availability of such results would most likely prompt doctors to also test the newborn’s heart and calcium levels.
The researchers conclude that their method shows it may one day be possible to diagnose all inherited and de novo genetic diseases non-invasively, that is using just the mother’s blood, without having to take samples from inside the uterus.
Co-author Dr Yair Blumenfeld, a clinical assistant professor of obstetrics and gynecology at Stanford Medical School, related how only a few years ago they were excited by being able to detect non-invasively whether a fetus had an abnormal number of chromosomes. But they also knew then this was just the tip of the iceberg, and the future would be about individual gene defects:
“This important study confirms our ability to detect individual fetal gene defects simply by testing mom’s blood,” said Blumenfeld.
The team is now working on developing the technology for clinical use, and Stanford has already filed a patent for it.
Funds from the Howard Hughes Medical Institute and the National Institute of Health helped pay for the study.
Written by Catharine Paddock PhD