A picture of a normal human karyotype is presented in Chapter 10. Such figures are obtained by taking dividing cells from the fetal sample and lysing them (breaking them open) on glass slides so that the individual mitotic chromosomes spread out in a loose field. After the slides are stained with dyes, the resulting clusters of chromosomes from each cell are photographed and examined. Skilled cytogenetic technicians begin with large photographs of each metaphase spread. Then they carefully cut the picture of each chromosome out of the photograph and match each pair of chromosomes side by side on a piece of mounting paper. The folks who do karyotyping in the cyto-genetics labs are truly gifted at pattern recognition.
Some disorders, such as autosomal trisomies, and sex chromosome anomalies, such as Turner (XO) and Klinefelter (XXY) syndromes, are easily picked up by this method. However, a good karyotype can also recognize more subtle aberrations, such as deficiencies or duplications for small regions of the genome, translocations of material between chromosomes, inversions of the material on a given chromosome, and the fusion of two ends of a given chromosome to form a ring. Although such anomalies are not common in humans, they do occur and they often have phenotypic consequences. For example, being heterozygous for a deletion of material on the short arm of chromosome 5, which is to say possessing only one copy of that material, results in a disorder known as cri-du-chat (or "cry of the cat") syndrome. This syndrome, recognizable because such infants mew like kittens when they cry, results in severe mental retardation and craniofacial anomalies. We have also noted previously the role of deletions in causing Prader-Willi and Angelman syndromes. Note that if the right culture conditions are used, it is possible to recognize the presence of "fragile sites," such as those regions at which chromosomal breakage is observed in fragile X syndrome patients.
One might also note that karyotyping sometimes reveals abnormalities, such as an XYY karyotype, whose effects are not clearly understood or defined. Other abnormalities may be found, such as balanced or reciprocal translocations that may not affect the health of the child but might well affect his or her ability to produce children. Some care is required in explaining such outcomes to the prospective parents. This point also applies when karyotyping anyone. A student who accidentally discovered that she carries a balanced translocation as the result of using her own cells for a routine lesson in how to do karyotypes found that even though she was phenotypically normal, the translocation offered a potential hazard to her fertility and the health of any children that she would have. Although it was possible to tell that there are potential health hazards for some of her offspring, simply looking at the rearranged chromosome structures under the microscope cannot indicate what form those health problems might take.
Karyotyping will also, by default, tell you the sex of the fetus. Curiously, prospective parents differ in whether they want to be told what sex was revealed by the karyotype. Parents often say that they prefer to be surprised in the delivery room regarding the sex of the baby and thus ask that the report of the results of a normal karyotype be limited to "everything looks fine." However, some parents want advance information on this point. One even finds the occasional case of a split decision between parents.
Once the fetus is identified as having a complex chromosomal rearrangement, an important question is: Exactly which chromosomal bits are involved in the rearrangement? Much is known about the consequences of extra copies of even small regions of a particular chromosome, so if we can go beyond telling that there is a rearragement to telling exactly which chromosomal regions are going to have too many or too few copies, we may be able to make some predictions about what the consequences will be. In some cases a simple karyotype is enough to identify the additional piece of DNA, but FISH (the use of a specific probe from one specific chromosomal region) or chromosome painting increases the chance that we will be able to get a specific answer to our questions about the baby's karyotype. There are some specific regions of the genome associated with well-characterized syndromes, so in some cases, important questions can be asked by FISH-ing with probes specific to the region in which deletions are known to cause traits such as velocardiofacial syndrome or diGeorge syndrome.
In a real sense, this section is simply a summary of the last thirty-three chapters. Suppose a couple's first child had Duchenne muscular dystrophy
(DMD) and the couple came to you asking about the DMD status of their second, unborn child. Karyotyping might provide some reassurance because a female fetus is very unlikely to be affected. If the fetus is male, the answer is less clear-cut because the odds of the child being affected are fifty percent if the mother is a known carrier. However, if you already know the nature of the DMD mutation borne by the first child and have a sample of fetal cells available from the second child, it is straightforward to determine whether this child carries the mutation. Now you can provide truly useful information to the parents. Very similar things can be done in the cases of quite a number of other diseases, such as cystic fibrosis, when it is known that the fetus is at risk for that disease. Tests are being developed rapidly for a host of other disorders for which tests were not previously available. Even if the gene is not yet cloned, a closely linked DNA marker can sometimes be used to diagnose the genetic state of the fetus if DNA from other family members is also tested. There is nothing special about fetal DNA, at least in terms of its chemical properties; any of the tests described so far can be used to assay the genetic state of a fetus.
It usually will make a big difference if the primary genetic defect has already been determined for affected family members and carriers before tackling prenatal diagnosis. For many, the test for a known mutation can be fast. However, as stated earlier, many genes are quite large. An open-ended search for an unknown mutation somewhere within one of these genes can take some time, precious time that you do not want to spend during the period in which prenatal testing takes place. For some genes, such as CF, tests have been developed that can identify a large number of known mutations but cannot detect rare mutations or new mutations not previously observed. For other genes, however, the development of testing has not advanced as far, and it could take too much time to determine the primary mutation on the time scale of the prenatal test.
Thus, if you are concerned about a genetic defect and want to include mutation screening as part of your family planning, it will work out much better if you start asking questions before you are pregnant. You may be told that a standard test is in place that can do everything you need done at the time of the prenatal test, or you may be told that you qualify for some type of "preimplantation" testing. However, depending on what the gene is and what the genetic defect is, beginning your inquiries ahead of time might give you important choices that might not be available if you wait until week twelve of the pregnancy. Of course, there are many cases (new mutations or recessive diseases that you don't realize are lurking in the genomes of both you and your spouse) that you don't even know you should ask about until the first child with a problem is born into a family. Even then, asking your relatives questions about the family medical history can sometimes offer a warning. If you have a cousin with cystic fibrosis and your spouse had a great uncle with cystic fibrosis, you should be asking yourself whether you want to talk to a member of a medical genetics team before the first pregnancy. Sometimes the test result will be the happiest one of all—that you are not carriers. However, if that is not the answer, being informed can save you from later saying, "If only I had asked."
This ability to do genetic testing is not a panacea. Indeed, the facility of such tests becomes most worrisome in terms of the material we have presented on the inheritance of complex traits. One worries about people in the near future attempting to test fetuses for DNA markers associated with traits such as mental illness, obesity, and sexual orientation. It is perhaps a rather personal set of prejudices, but we draw a distinction here between testing for traits an individual will express and which will greatly diminish their quality of and length of life, such as DMD or fragile X, and those traits that they might express and whose effects on their quality of life are hard to assess.
Aren't there diseases for which the responsible genes are neither mapped nor cloned? Yes, there are, and some of these disorders can be diagnosed by biochemical or enzymatic assays performed on fetal tissues. Such tests are briefly described in the next section.
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