Genetic Testing: Applications for Genetic Testing

Genetic testing is used most often for newborn screening. Every year, millions of newborn babies have their blood samples tested for potentially serious genetic diseases.

An individual who has a gene associated with a disease but never exhibits any symptoms of the disease is called a carrier. A carrier is a person who is not affected by the mutated gene he or she possesses, but can pass the gene to an offspring. Genetic tests have been developed that tell prospective parents whether or not they are carriers of certain diseases. If one or both parents are a carrier, the risk of passing the disease to a child can be predicted.

To predict the risk, it is necessary to know if the gene in question is autosomal or sex-linked. If the gene is carried on any one of chromosomes 1–22, the resulting disease is called an autosomal disease. If the gene is carried on the X or Y chromosome, it is called a sex-linked disease.

Sex-linked diseases, such as the bleeding condition hemophilia, are usually carried on the X chromosome. A woman who carries a disease-associated mutated gene on one of her X chromosomes, has a 50% chance of passing that gene to her son. A son who inherits that gene will develop the disease because he does not have another normal copy of the gene on a second X chromosome to compensate for the mutated copy. A daughter who inherits the disease associated mutated gene from her mother, on one of her X chromosomes will be at risk for having a son affected with the disease.

The risk of passing an autosomal disease to a child depends on whether the gene is dominant or recessive. A prospective parent carrying a dominant gene, has a 50% chance of passing the gene to a child. A child needs to receive only one copy of the mutated gene to be affected by the disease.

If the gene is recessive, a child needs to receive two copies of the mutated gene, one from each parent, to be affected by the disease. When both prospective parents are carriers, their child has a 25% chance of inheriting two copies of the mutated gene and being affected by the disease; a 50% chance of inheriting one copy of the mutated gene, and being a carrier of the disease but not affected; and a 25% chance of inheriting two normal genes. When only one prospective parent is a carrier, a child has a 50% chance of inheriting one mutated gene and being an unaffected carrier of the disease, and a 50% chance of inheriting two normal genes.

Cystic fibrosis is a disease that affects the lungs and pancreas and is discovered in early childhood. It is the most common autosomal recessive genetic disease found in the caucasian population: one in 25 people of Northern European ancestry are carriers of a mutated cystic fibrosis gene. The gene, located on chromosome 7, was identified in 1989.

The gene mutation for cystic fibrosis is detected by a direct DNA test. Over 600 mutations of the cystic fibrosis gene have been found; each of these mutations cause the same disease. Tests are available for the most common mutations. Tests that check for the 86 of the most common mutations in the Caucasian population will detect 90% of carriers for cystic fibrosis. (The percentage of mutations detected varies according to the individual's ethnic background). If a person tests negative, it is likely, but not guaranteed that he or she does not have the gene. Both prospective parents must be carriers of the gene to have a child with cystic fibrosis.

Tay-Sachs disease, also autosomal recessive, affects children primarily of Ashkenazi Jewish descent. Children with this disease die between the ages of two and five. This disease was previously detected by looking for a missing enzyme. The mutated gene has now been identified and can be detected using direct DNA mutation analysis.

Not all genetic diseases show their effect immediately at birth or early in childhood. Although the gene mutation is present at birth, some diseases do-not appear until adulthood. If a specific mutated gene responsible for a late-onset disease has been identified, a person from an affected family can be tested before symptoms appear.

Huntington's disease is one example of a late-onset autosomal dominant disease. Its symptoms of mental confusion and abnormal body movements do not appear until middle to late adulthood. The chromosome location of the gene responsible for Huntington's chorea was located in 1983 after studying the DNA from a large Venezuelan family affected by the disease. Ten years later the gene was identified. A test is now available to detect the presence of the expanded base pair sequence responsible for causing the disease. The presence of this expanded sequence means the person will develop the disease.

Another late onset disease, Alzheimer's does not have as well a understood genetic cause as Huntington's disease. The specific genetic cause of Alzheimer's disease is not as clear. Although many cases appear to be inherited in an autosomal dominant pattern, many cases exist as single incidents in a family. Like Huntington's, symptoms of mental deterioration first appear in adulthood. Genetic research has found an association between this disease and genes on four different chromosomes. The validity of looking for these genes in a person without symptoms or without family history of the disease is still being studied.

CANCER SUSCEPTIBILITY TESTING. Cancer can result from an inherited (germline) mutated gene or a gene that mutated sometime during a person's lifetime (acquired mutation). Some genes, called tumor suppressor genes, produce proteins that protect the body from cancer. If one of these genes develops a mutation, it is unable to produce the protective protein. If the second copy of the gene is normal, its action may be sufficient to continue production, but if that gene later also develops a mutation, the person is vulnerable to cancer. Other genes, called oncogenes, are involved in the normal growth of cells. A mutation in an oncogene can cause too much growth, the beginning of cancer.

Direct DNA tests are currently available to look for gene mutations identified and linked to several kinds of cancer. People with a family history of these cancers are those most likely to be tested. If one of these mutated genes is found, the person is more susceptible to developing the cancer. The likelihood that the person will develop the cancer, even with the mutated gene, is not always known because other genetic and environmental factors are also involved in the development of cancer.

Cancer susceptibility tests are most useful when a positive test result can be followed with clear treatment options. In families with familial polyposis of the colon, testing a child for a mutated APC gene can reveal whether or not the child needs frequent monitoring for the disease. In families with potentially fatal familial medullary thyroid cancer or multiple endocrine neoplasia type 2, finding a mutated RET gene in a child provides the opportunity for that child to have preventive removal of the thyroid gland. In the same way, MSH1 and MSH2 mutations can reveal which members in an affected family are vulnerable to familiar colorectal cancer and would benefit from aggressive monitoring.

In 1994, a mutation linked to early-onset familial breast and ovarian cancer was identified. BRCA1 is located on chromosome 17. Women with a mutated form of this gene have an increased risk of developing breast and ovarian cancer. A second related gene, BRCA2, was later discovered. Located on chromosome 13, it also carries increased risk of breast and ovarian cancer. Although both genes are rare in the general population, they are slightly more common in women of Ashkenazi Jewish descent.

When a woman is found to have a mutation of one of these genes, the likelihood that she will get breast or ovarian cancer increases, but not to 100%. Other genetic and environmental factors influence the outcome.

Testing for these genes is most valuable in families where a mutation has already been found. BRCA1 and BRCA2 are large genes; BRCA1 includes 100,000 bases. More than 120 mutations to this gene have been discovered, but a mutation could occur in any one of the bases. Studies show tests for these genes may miss 30% of existing mutations. The rate of missed mutations, the unknown disease likelihood in spite of a positive result, and the lack of a clear preventive response to a positive result, make the value of this test for the general population uncertain.

Chromosome analysis can be done on fetal cells primarily when the mother is age 35 or older at the time of delivery, experienced multiple miscarriages, or reports a family history of a genetic abnormality. Prenatal testing is done on the fetal cells from a chorionic villi sampling (from the baby's developing placenta) at 9–12 weeks or from the amniotic fluid (the fluid surrounding the baby) at 15–22 weeks of pregnancy. Cells from amniotic fluid grow for seven to 10 days before they are ready to be analyzed. Chorionic villi cells have the potential to grow faster and can be analyzed sooner.

Chromosome analysis using blood cells is done on a child who is born with or later develops signs of mental retardation or physical malformation. In the older child, chromosome analysis may be done to investigate developmental delays.

Extra or missing chromosomes cause mental and physical abnormalities. A child born with an extra chromosome 21 (trisomy 21) has Down syndrome. An extra chromosome 13 or 18 also produce well known syndromes. A missing X chromosome causes Turner syndrome and an extra X in a male causes Klinefelter syndrome. Other abnormalities are caused by extra or missing pieces of chromosomes. Fragile X syndrome is a sex-linked disease, causing mental retardation in males.

Chromosome material may also be rearranged, such as the end of chromosome 1 moved to the end of chromosome 3.This is called a chromosomal translocation. If no material is added or deleted in the exchange, the person may not be affected. Such an exchange, however, can cause infertility or abnormalities if passed to children.

Evaluation of a man and woman's infertility or repeated miscarriages will include blood studies of both to check for a chromosome translocation. Many chromosome abnormalities are incompatible with life; babies with these abnormalities often miscarrry during the first trimester. Cells from a baby that died before birth can be studied to look for chromosome abnormalities that may have caused the death.

Certain cancers, particularly leukemia and lymphoma, are associated with changes in chromosomes: extra or missing complete chromosomes, extra or missing portions of chromosomes, or exchanges of material (translocations) between chromosomes. Studies show that the locations of the chromosome breaks are at locations of tumor suppressor genes or oncogenes.

Chromosome analysis on cells from blood, bone marrow, or solid tumor helps diagnose certain kinds of leukemia and lymphoma and often helps predict how well the person will respond to treatment. After treatment has begun, periodic monitoring of these chromosome changes in the blood and bone marrow gives the physician information as to the effectiveness of the treatment.

A well-known chromosome rearrangement is found in chronic myelogenous leukemia. This leukemia is associated with an exchange of material between chromosomes 9 and 22. The resulting smaller chromosome 22 is called the Philadelphia chromosome.

— Katherine S. Hunt, MS