The level of phenylalanine in the blood is an indirect measure of phenylalanine hydroxylase activity in the liver. But how can we screen for *genetic diseases that are not detectable by blood tests? What if blood is difficult to obtain, as it is in a fetus? How are genetic abnormalities in heterozygotes, who express the normal protein at some level, identified?

DNA testing is the direct analysis of DNA for a mutation, and it offers the most direct and accurate way of detecting an abnormal allele. Now that the mutations responsible for many human diseases have been identified, any cell in the body can be examined at any time of life for mutations. The amplification power of PCR means that only one or a few cells are needed for testing. These methods work best for diseases caused by only one or a few different mutations.

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Consider, for example, two parents who are both heterozygous for the cystic fibrosis allele but who want to have a healthy child. If treated with the appropriate hormones, the mother can be induced to “superovulate,” releasing several eggs. Eggs can be harvested from the mother and artificially inseminated. The fertilized egg can be allowed to divide to the eight-cell stage. If one of these embryonic cells is removed, it can be tested for the presence of the cystic fibrosis allele. If the test is negative, the remaining seven-cell embryo can be implanted in the mother’s womb, where with luck it will develop normally.

Such preimplantation screening is performed only rarely. More typical are analyses of fetal cells after normal fertilization and implantation in the womb. Fetal cells or even DNA that has leaked out of dead cells can be analyzed at about the tenth week of pregnancy by chorionic villus sampling, or during the thirteenth to seventeenth weeks by amniocentesis. In either case, only a few fetal cells are necessary to perform DNA testing. Recently, very sensitive methods were developed so that DNA testing can be done with the few fetal cells that are released into the mother’s blood. A 10-milliliter blood sample from a pregnant woman has enough fetal cells for the analysis of many disorders, including Down syndrome and cystic fibrosis. This relatively noninvasive procedure could replace amniocentesis and chorionic villus sampling—which both carry a slight risk of causing a miscarriage—in the near future.

DNA testing can also be performed with newborns. The blood samples used for screening for PKU and other disorders contain enough of the baby’s blood cells to permit DNA analysis using PCR-based techniques. DNA analysis is now being used to screen for sickle-cell disease and cystic fibrosis; similar tests for other diseases will surely follow. Of the numerous methods of DNA testing available, we will describe DNA hybridization, using sickle-cell anemia as an example.