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Chromosomal analysis

Vf X ff^ft sample of amniotic fluid from a pregnant woman ( FIGURE 6.16). Amniotic fluid — the substance that fills the amniotic sac and surrounds the developing fetus — contains fetal cells that can be used for genetic testing.

Amniocentesis is routinely performed as an outpatient procedure with the use of a local or no anesthetic. First, ultrasonography is used to locate the position of the fetus in the uterus. Next, a long, sterile needle is inserted through the abdominal wall into the amniotic sac (see Figure 6.16), and a small amount of amniotic fluid is withdrawn through the needle. Fetal cells are separated from the amniotic fluid and placed in a culture medium that stimulates them to grow and divide. Genetic tests are then performed on the cultured cells. Complications with amniocentesis (mostly miscarriage) are rare, arising in only about 1 in 400 procedures.

Chorionic villus sampling A major disadvantage with amniocentesis is that it is routinely performed in about the 16th week of a pregnancy, (although many obstetricians now successfully perform amniocentesis several weeks earlier). The cells obtained with amniocentesis must then be cultured before genetic tests can be performed, requiring yet more time. For these reasons, genetic information about the fetus may not be available until the 17th or 18th week of pregnancy. By this stage, abortion carries a risk of complications and may be stressful for the parents. Chorionic villus sampling (CVS) can be performed earlier (between the 10th and 11th weeks of pregnancy) and collects more fetal tissue, which eliminates the necessity of culturing the cells.

In CVS, a catheter — a soft plastic tube — is inserted into the vagina ( FIGURE 6.17) and, with the use of ultrasound for guidance, is pushed through the cervix into the uterus. The tip of the tube is placed into contact with the chorion, the outer layer of the placenta. Suction is then applied, and a small piece of the chorion is removed. Although the chorion is composed of fetal cells, it is a part of the placenta that is expelled from the uterus after birth; so the removal of a small sample does not endanger the fetus. The tissue that is removed contains millions of actively dividing cells that can be used directly in many genetic tests. Chorionic villus sampling has a somewhat higher risk of complication than that of amniocentesis; the results of several studies suggest that this procedure may increase the incidence of limb defects in the fetus when performed earlier than 10 weeks of gestation.

Fetal cells obtained by amniocentesis or by CVS can used to prepare a karyotype, which is a picture of a complete set of metaphase chromosomes. Karyotypes can be studied for chromosome abnormalities (Chapter 9). Biochemical analyses can be conducted on fetal cells to determine the presence of particular metabolic products of genes. For genetic diseases in which the DNA sequence of the causative gene has been determined, the DNA sequence (DNA testing; Chapter 18) can be examined for defective alleles.

Maternal blood tests Some genetic conditions can be detected by performing a blood test on the mother (maternal blood testing). For instance, a-fetoprotein is normally produced by the fetus during development and is present in the fetal blood, the amniotic fluid, and the mother's blood during pregnancy. The level of a-fetoprotein is significantly higher than normal when the fetus has a neural-tube or one of several other disorders. Some chromosome l'| CVS [à Using ultrasound for performed early in preganancy.

guidance, a catheter is inserted through the vagina and cervix and into the uterus

^ ...where it is placed into contact with the chorion, the outer layer of the placenta.

^ Suction removes a small piece of the chorion.

6.17 Chorionic villus sampling is another procedure for obtaining fetal cells for genetic testing.

5| Cells of the chorion are used directly for many genetic tests, and culturing is not required.

l'| CVS [à Using ultrasound for performed early in preganancy.

guidance, a catheter is inserted through the vagina and cervix and into the uterus

^ ...where it is placed into contact with the chorion, the outer layer of the placenta.

^ Suction removes a small piece of the chorion.

5| Cells of the chorion are used directly for many genetic tests, and culturing is not required.

Chromosomal analysis

abnormalities produce lower-than-normal levels of a-feto-protein. Measuring the amount of a-fetoprotein in the mother's blood gives an indication of these conditions. However, because other factors affect the amount of a-fetoprotein in maternal blood, a high or low level by itself does not necessarily indicate a problem. Thus, when a blood test indicates that the amount of a-fetoprotein is abnormal, follow-up tests (additional a-fetoprotein determinations, ultrasound, amniocentesis, or all three) are usually performed.

Fetal cell sorting Prenatal tests that utilize only maternal blood are highly desirable because they are noninvasive and pose no risk to the fetus. During pregnancy, a few fetal cells are released into the mother's circulatory system, where they mix and circulate with her blood. Recent advances have made it possible to separate fetal cells from a maternal blood sample (a procedure called fetal cell sorting). With the use of lasers and automated cell-sorting machines, fetal cells can be detected and separated from maternal blood cells. The fetal cells obtained can be cultured for chromosome analysis or used as a source of fetal DNA for molecular testing (see p. 000 in Chapter 18).

A large number of genetic diseases can now be detected prenatally (Table 6.5), and the number is growing rapidly as new disease-causing genes are isolated. The Human Genome Project (Chapter 18) has accelerated the rate at which new genes are being isolated and new genetic tests are being developed. In spite of these advances, prenatal tests are still not available for many common genetic diseases, and no test can guarantee that a "perfect" child will be born.

Preimplantation genetic diagnosis Prenatal genetic tests provide today's couples with increasing amounts of information about the health of their future children. New reproductive technologies also provide couples with options for using this information. One of these technologies is in vitro fertilization. In this procedure, hormones are used to induce ovulation. The ovulated eggs are surgically removed from the surface of the ovary, placed in a laboratory dish, and fertilized with sperm. The resulting embryo is then implanted into the uterus. Thousands of babies resulting from in vitro fertilization have now been born.

Genetic testing can be combined with in vitro fertilization to allow implantation of embryos that are free of a specific genetic defect. Called preimplantation genetic diagnosis, (PGD), this technique allows people who carry a genetic defect to avoid producing a child with the disorder. For example, when a woman is a carrier of an X-linked recessive disease, approximately half of her sons are expected to have the disease. Through in vitro fertilization and preimplantation testing, it is possible to select an embryo without the disorder for implantation in her uterus.

The procedure begins with the production of several single-celled embryos through in vitro fertilization. The embryos are allowed to divide several times until they reach the 8 or 16-cell stage. At this point, one cell is removed from each embryo and tested for the genetic abnormality. Removing a single cell at this early stage does not harm the embryo. After determination of which embryos are free of

[Table 6.5 Examples of genetic diseases and disorders that can be detected prenatally 1

and the techniques used in their detection

Disorder

Method of Detection

Chromosome abnormalities

Examination of a karyotype from cells obtained by

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