DNA Blueprint for Fetus Built Using Tests of Parents

By ANDREW POLLACK

Published: June 6, 2012

For the first time, researchers have determined virtually the entire genome of a fetus using only a blood sample from the pregnant woman and a saliva specimen from the father.

Clare McLean/University of Washington

Jay Shendure, a professor at the University of Washington, supervised the research team.

Times Topics: Research | DNA

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Clare McLean/University of Washington

The Northwest Genome Sequencing Center at the University of Washington.

The accomplishment heralds an era in which parents might find it easier to know the complete DNA blueprint of a child months before it is born.

That would allow thousands of genetic diseases to be detected prenatally. But the ability to know so much about an unborn child is likely to raise serious ethical considerations as well. It could increase abortions for reasons that have little to do with medical issues and more to do with parental preferences for traits in children.

“It’s an extraordinary piece of technology, really quite remarkable,” said Peter Benn, professor of genetics and developmental biology at the University of Connecticut, who was not involved in the work. “What I see in this paper is a glance into the future.”

The paper, published Wednesday in the journal Science Translational Medicine, was written by genome scientists at the University of Washington. They took advantage of new high-speed DNA sequencing and some statistical and computational acrobatics to deduce the DNA sequence of the fetus with about 98 percent accuracy.

The process is not practical, affordable or accurate enough for use now, experts said. The University of Washington researchers estimated that it would cost $20,000 to $50,000 to do one fetal genome today.

But the cost of DNA sequencing is falling at a blistering pace, and accuracy is improving as well. The researchers estimated that the procedure could be widely available in three to five years. Others said it would take somewhat longer.

It is already possible to determine the DNA sequence of a fetus by acquiring fetal cells through amniocentesis or chorionic villus sampling, which involves testing the placental tissue. But these procedures are invasive and carry a slight risk of inducing a miscarriage.

For couples worried about passing on a genetic disease, it is also possible to use in vitro fertilization and have an embryo genetically tested before implantation into the womb.

But the technique described in the paper would not require complete cells from the fetus and would make such DNA testing easier and less risky.

“If this sort of thing is ever to be used on a widespread basis, I think it necessarily has to be noninvasive,” said Jay Shendure, associate professor of genome sciences at the University of Washington, who supervised the research team.

The genome was determined from blood samples taken 18.5 weeks into the pregnancy, although the researchers said the technique could probably be applied in the first trimester, as early as or even earlier than some invasive techniques.

The technique takes advantage of the discovery in the 1990s that fragments of DNA from the fetus can be found in a pregnant woman’s blood plasma, probably the result of fetal cells dying and breaking apart.

These fragments can be genetically analyzed, providing that the fetal DNA fragments can be distinguished from the far more numerous fragments that come from the mother herself.

The analysis of fetal DNA fragments found in a pregnant woman’s blood is already used in new commercially available tests of the fetus’s gender, its paternity and whether it has Down syndrome. But reconstructing an entire genome from DNA fragments is much more difficult.

Such information would allow detection of so-called Mendelian disorders, like cystic fibrosis, Tay-Sachs disease and Marfan syndrome, which are caused by mutations in a single gene.

More than 3,000 such diseases collectively occur in about 1 percent of births. The mutations can be inherited from the parents or they can arise spontaneously in the fetus.

Researchers led by Dennis Lo at the Chinese University of Hong Kong first showed in 2010 that reconstructing a fetal genome would be possible. Other work toward this goal has been done by Stephen Quake and colleagues at Stanford University.

But Dr. Lo’s team used a maternal sample obtained invasively. And it could determine only the inherited mutations, not the spontaneous ones.

The University of Washington researchers, using an approach partly developed by a graduate student, Jacob O. Kitzman, did not need an invasive test. And they were able to detect 39 of 44 such spontaneous mutations, though with a huge number of false positives.

“This will be a step toward having a better and better prenatal diagnosis that detects more and more at a reliable cost,” said Dr. Arthur L. Beaudet, chairman of molecular and human genetics at Baylor College of Medicine in Houston.

Dr. Beaudet, who was not involved in the work, said that spontaneous mutations account for about 10 percent of cases of mental retardation and other learning disabilities.

The ability to sequence an entire fetal genome is likely to raise numerous issues. “There are some scenarios that are extremely troubling,” said Marcy Darnovsky, associate executive director of the Center for Genetics and Society, a public interest group in Berkeley, Calif. The tests will spur questions on “who deserves to be born,” she said.