BioEd Online

A non-invasive blood test can now detect the gene for the fatal disease beta-thalassemia in a growing fetus. Its developers believe that the technique could be applied to a range of other diseases, overcoming the need for a more invasive procedure called amniocentesis.

Screening a mother's blood can already determine whether unborn children have certain hereditary diseases. But current screens can only detect large-scale irregularities in the baby's chromosomes, such as those found in Down syndrome, says Sinuhe Hahn, a molecular biologist from the University Women's Hospital in Basel, Switzerland.

Doctors use amniocentesis to spot single-gene mutations, such as the ones that cause beta-thalassemia. The test involves inserting a needle in the mother's abdomen to draw amniotic fluid out of the womb. But the invasive method can lead to damage or loss of the baby in up to 1% of cases.

Hahn and his colleagues have found that trace fragments of fetal DNA can be separated from the mother's genetic material in her blood. This allows them to pinpoint single mutations in the baby's DNA, which is normally swamped by the mother's own DNA.

Size separation

The researchers took blood samples from 32 women of southern Italy who were about 12 weeks into their pregnancies. Family histories suggested that the babies were at risk of being born with beta-thalassemia, a fatal hereditary disease that stops red blood cells producing the vital oxygen-carrying haemoglobin molecule.

Last year, Hahn's team found that a mother's DNA fragments tend to be much larger than those of her unborn child. Although the blood of a mother and fetus do not mix directly, the placenta sheds about 8 grams of tissue a day, releasing the baby's DNA into the mother's blood.

So the researchers separated the maternal and fetal DNA in blood samples using a process called electrophoresis, in which molecules are dragged though a long strip of gel by an electrical voltage. The smallest fragments were almost entirely from the fetus, allowing the researchers to correctly identify the presence or absence of beta-thalassemia mutation 93.8% of the time. The results appear in the Journal of the American Medical Association¹.

Recessive trait

The gene responsible for beta-thalassemia is recessive, so a parent can carry one copy of the gene mutation without having the disease. But if a child receives two mutated copies, one from each parent, he or she will ultimately develop the disorder. There are more than 200 known mutations of the crucial gene, any combination of which will lead to beta-thalassemia.

Despite the difference in fragment size, there is still a risk that the 'fetal' DNA could in fact belong to the mother, so finding that it contained her particular genetic mutation would not be conclusive. Instead, explains Hahn, the researchers search for evidence that this DNA contains the father's mutation. In the unlikely event that the parents have exactly the same mutation, the test would not work, but Hahn believes that further research will overcome this problem.

Aubrey Milunsky, director of the Center for Human Genetics at the Boston University School of Medicine, Massachusetts, notes that even amniocentesis can require paternal blood to establish certain point mutations. But he cautions that the new technique has to prove itself against the current gold standard: "This is not yet ready for prime time," he says.

The researchers are now trying to develop the same technique to identify cystic fibrosis and a metabolic disorder called Tay-Sachs disease, which can cause severe mental retardation and death.

"And the process is still tedious," Hahn adds. "We would like to automate it and be able to separate DNA rapidly with a machine."