DNA is a very large molecule composed of two closely entwined strings of small molecules. Diseases arise from mutations (Greek for changes) in the DNA. A mutation causes one or more of the small molecules to be missing or altered in one or both strings. When the mutation involves only one of the small molecules, techniques for finding the alteration are very laborious, because there are three billion of the small molecules in each person's DNA. At the other extreme, some mutations involve such large segments of DNA that they are visible under the microscope. There are numerous laboratory tricks and techniques used to detect the smaller mutations.
Most DNA tests are tests for constitutional mutations. That type of mutation is inherited, so it is present at the moment of conception and therefore occurs in all cells in the body. Any readily available source of living cells can be tested. Most commonly, blood cells are used. The blood is drawn from a vein into a glass Vacutainer tube containing a preservative, such as liquid EDTA or acid-citrate solution. The blood specimen is usually drawn at a local laboratory and mailed to a reference laboratory. The reference laboratory usually waits until it receives many specimens and then processes them all at once in order to conserve labor and chemicals. After the test is completed, the report is returned to the local laboratory.
In some diseases, the mutation is focal, which means that it is present only in certain body cells (tissues). An example of a focal mutation is a mutation that causes a tumor. The DNA change that causes a tumor only occurs in cells that make up the tumor and not in other cells of the body. In this case, additional steps are required in the testing process. A biopsy (piece) of the tissue must be obtained surgically. Simple liquid solutions may not suffice for preservation of this tissue, so more exotic mechanisms can be required such as freezing in liquid nitrogen. This makes mailing difficult. The added steps make the process expensive.
When is DNA testing needed? There are several reasons, or indications, why DNA testing of an individual or a family may be needed.
DNA testing for accurate diagnosis. Medically, ensuring the accuracy of a disease diagnosis is the most important reason for DNA testing, because many diseases can occur in a form that is difficult to recognize. In other cases, different diseases may be so similar that it is difficult to decide which is present. It is important to be certain about a diagnosis in order to choose the correct treatment. Prognosis, or knowledge about what problems the disease will cause in the future, is also important. Finally, there are different genetic mechanisms of disease that may cause the disease to occur in different relatives or children.
DNA testing to prevent or delay disease. Sometimes there are indications for DNA testing when no disease is present. In a family in which a genetic disease is known to exist, DNA testing may be able to identify which relatives may get the disease. In some groups, particular genetic diseases are so common that testing might be done on everybody. This type of testing is of greatest value if there is some form of intervention that might either prevent the disease or delay its onset. This intervention could be a lifestyle change, medication, or surgery.
Even if there is no intervention available, testing of this type can identify persons whose children could be affected. In these cases, there may be a prenatal DNA test that can determine if a fetus is affected by the disease. Preimplantation DNA testing can be done on early embryos resulting from in vitro fertilization in order to select those that are free from a particular serious genetic disease. Because many additional procedures are required, however, preimplantation testing is expensive and is not usually covered by insurance.
A carrier is a person who does not have a particular genetic disease but who can pass the genetic mutation that causes the disease to his or her children. Carrier testing can be offered (1) to individuals who have family members with a genetic disease, (2) to family members of an identified carrier, and (3) to members of groups known to have a higher carrier rate for a particular disease. Carrier testing identifies persons who have a mutation for a disease inherited in an autosomal recessive or X-linked recessive manner. Although the mutation does not cause the disease in carriers, it confers a high risk of transmitting the disease to their children. Carrier testing helps parents understand these risks and make informed decisions.
Social and Legal Indications for DNA testing. There are also legal and social indications for DNA testing. If paternity is uncertain, DNA testing can identify the biological father. This can be important in determining responsibility for financial support and for the legalities of inheritance. When family history is absent or inadequate, DNA testing can determine if specific genetic diseases exist in children who are available for adoption. Certain genetic diseases may appear identical to those produced by alleged malpractice, and DNA testing can exonerate the accused physician. The same is true for product liability defenses.
Organ Transplantation. DNA zygosity testing can be used to identify a donor for organ transplant. (Identical, or monozygotic, twins are logically the best donors). DNA banking is offered by some of the same laboratories that perform DNA testing. DNA banking involves extracting DNA from cells and freezing or refrigerating it for future testing. DNA is stable even outside of cells and therefore can be stored for years. DNA banking may be offered to terminally ill patients with a known or suspected genetic disease, persons with a genetic disorder for which no testing is yet available, or persons who do not presently wish to pursue available testing but would like to reserve the option for the future.
How much does DNA testing cost? Costs for DNA testing can range from reasonable to exorbitant. For easy-to-detect constitutional mutations, the cost is approximately the same as for hormone tests - $200, more or less, per test. Difficult tests and tests for focal mutations can cost thousands of dollars. Most insurers cover only the less expensive tests. The "turnaround time" or the time from specimen collection to reporting is usually a matter of weeks or months.
Are there problems associated with DNA testing? Interpretation of the DNA testing report is usually straightforward but may require some knowledge of genetics and disease processes. Because different mutations in different locations in DNA can produce essentially identical diseases, the mutational repertoire of most genetic diseases can present problems. Also, most DNA tests are exquisitely specific: A test for a one mutation may miss a different mutation in the same gene. This problem has led to the saying, "Absence of proof is not proof of absence." Hence, DNA testing is sometimes a gamble.
Testing for some genetic diseases requires linkage analysis. Instead of searching for the exact mutation that causes a disease, linkage is based on testing for harmless mutations that surround the area of DNA in which the disease-causing mutation occurs. Linkage analysis can detect disease-causing mutations of any type, but the testing of several relatives is required to accurately determine the area of DNA with the mutation. This is costly and carries risks of infringement of privacy, including disclosure of non-paternity. In addition, the body's normal process of safely exchanging similar parts of DNA molecules (called crossing over) during the production of sperm and egg cells in the parent can, simply by chance, interfere with the accuracy of the analysis of a child's DNA. Again, linkage analysis is a gamble, but a much more expensive one because of the requirement of testing for several mutations in several people.
At present, DNA tests are available for about 400 disease-causing genes. However, that number includes numerous cases in which the same or very similar diseases are caused by different genes, so the actual number of genetic diseases for which a DNA test is available is much lower. For example, there are DNA tests for 12 different genes that cause the disease called epidemolysis bullosa. There are clinical differences in the forms of the disease, so a physician does not necessarily have to order all 12 tests. All of the different forms of all genetics diseases are described at the website, Online Mendelian Inheritance in Man (OMIM), which is accessed at http://www3.ncbi.nlm.nih.gov/Omim/.
Large national referral laboratories (like LabCorp and the Mayo Clinic) offer the most frequently used tests and may already be on contract with a local laboratory. In all, there are about 400 certified laboratories that provide clinical DNA testing. (These laboratories should not to be confused with research testing laboratories from which results are not certified and are not necessarily released to the doctor or patient). At present, there is no print edition of a guide to the laboratories and tests. An online list is available to healthcare providers, who must register and receive a password: http://www.genetests.org/.