New Down syndrome test less risky than amniocentesis

Pregnant women worried about their babies' genetic health face a tough decision: get prenatal gene testing and risk miscarriage, or skip the tests and miss the chance to learn of genetic defects before birth.

But a new prenatal test could make this dilemma obsolete. The new method, developed by scientists at Stanford, the Howard Hughes Medical Institute and Lucile Packard Children's Hospital, requires only a maternal blood sample to spot chromosomal disorders such as Down syndrome.

'Right now, people are risking their pregnancies to get this information,' said Yair Blumenfeld, MD, a postdoctoral fellow in obstetrics and gynecology and co-author of a paper describing the technique. Current prenatal gene tests, such as amniocentesis and chorionic villus sampling, require inserting a needle in the uterus and carry a miscarriage risk of around half a percent.

'Non-invasive testing will be much safer than current approaches,' said Stephen Quake, PhD, professor of bioengineering and the study's senior author. The new technique, which takes advantage of fragments of fetal DNA in the woman's blood, was published online Oct. 6 in the Proceedings of the National Academy of Sciences. Safety may not be the only gain. Quake hopes the test will spot genetic problems much earlier in gestation than the other methods.

The new method scans for fetal aneuploidy, an abnormality in the number of fetal chromosomes. Humans typically inherit 46 chromosomes, half from each parent. Errors in chromosome number cause serious problems in physical and mental development. Down syndrome, for example, arises from an extra copy of chromosome 21.

The Stanford/Packard team developed a way to count chromosomes using bits of fetal DNA in a pregnant woman's blood. Other scientists had struggled to tease these tiny genetic clues apart from a mom's DNA, said Quake, who is also an HHMI investigator. His team made an ingenious simplification: their new method has no need to distinguish between maternal and fetal DNA.

First, using samples from 12 women with aneuploid pregnancies and six with normal pregnancies, the researchers separated maternal blood into cells and plasma. They discarded the blood cells, focusing on the liquid plasma's DNA fragments, which come from both the mom and the fetus. They counted the number of DNA fragments and used DNA sequencing to read each one.

'You randomly sequence whatever is there,' said Christina Fan, a doctoral student in bioengineering who was the study's lead author. The DNA fragments are 25-30 base pairs long, she said, long enough to match each fragment to a specific chromosome. The researchers tallied how many gene fragments originated from each chromosome. Women with Down syndrome pregnancies had more chromosome-21 fragments in their blood than women with normal pregnancies. Other forms of aneuploidy could be detected, too.

Because fetal DNA shows up in maternal blood quite early in pregnancy, the team says its technique could provide a much earlier diagnosis for aneuploidy than now available. 'The earlier you know you've got a fetus with Down syndrome, the better able you are to prepare,' Quake said, noting that the benefit holds both for women who keep and those who terminate such pregnancies.

Quake estimates it taking another two to three years before the test would become available. The next step, the scientists say, is to repeat their study in a larger number of women. If the findings are confirmed, it would be simple and inexpensive to use the test in clinical settings, especially as other forms of genetic testing also become popular. 'This technique is on the leading edge of a flood of different ways that rapid DNA sequencing will be used in medicine,' he said.

Stanford is filing a patent application for the technique; Quake consults for two potential licensees. In addition to Fan and Blumenfeld, the team included Usha Chitkara, MD, professor of obstetrics and gynecology at Stanford and Packard Children's, and Louanne Hudgins, MD, director of perinatal genetics at Packard Children's and professor of pediatrics. The study was funded by the Wallace H. Coulter Foundation and an NIH Director's Pioneer Award.