A Basic Guide to Genetic Testing

Basic Genetics
What is genetic testing?
What are the different types of genetic tests?
Are genetic tests always accurate?
Why would a physician offer genetic testing?
What other things should I be aware of when considering genetic testing?

Basic Genetics
To understand the different types of genetic tests, it is helpful to understand basic genetics. Genetics is the science of heredity, or the study of how certain traits are passed from one generation to the next. These traits include physical characteristics, such as eye and hair color, and other characteristics, such as the tendency for a person to develop a certain genetic disease.

In most types of cells, genetic information is organized into structures called chromosomes. Most humans have 46 chromosomes, organized into 23 pairs. In each pair, one chromosome comes from the male parent and one from the female parent.¹

Each chromosome contains many pieces of genetic material called genes², which are important in body development and function. Genes determine the unique traits of each individual.

Individuals carry two genes for each trait, one from the father and one from the mother. One of these two genes is sometimes dominant over the other. This dominant gene will mask the expression of the other gene, called the recessive gene.²

A dominant gene needs to be inherited from only one parent for the trait it controls to be seen in the offspring. However, a recessive gene must be received from both parents for it to be expressed.²

A carrier of a disease is someone who has one copy of the gene or mutation for a recessive disease. This person does not have symptoms of the disease, but is capable of having a baby who is affected if he or she has a child with another carrier of the same disease.^2,3

1. Gardner RJ, Sutherland GR. Chromosome Abnormalities and Genetic Counseling. In: Oxford Monographs on Medical Genetics No. 29. New York, NY: Oxford University Press;1996.
2. Thompson MW, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1991.
3. Harper PS. Practical Genetic Counseling. Oxford, England; Butterworth-Heinemann Ltd; 1994.

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What is genetic testing?
Genetic testing is a specific type of laboratory testing performed on body tissues or fluids, such as blood. The tests help a physician determine if a person has a genetic disorder, is a carrier of a genetic disease, or has a predisposition to develop a genetic problem.

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What are the different types of genetic tests?
Genetic testing can look at chromosomes, genes, or proteins. There are four main categories of testing and your physician may order one of these types of tests depending on your specific condition.

Cytogenetic Testing:This means "chromosome study". Cytogenetic testing allows a scientist to look at the number or shape of chromosomes present in a patient's sample. Cytogenetic testing is useful when looking at the chromosomes as a whole, but it does not provide any information about specific genes or proteins that may be associated with a genetic disease.^1,2

An example of cytogenetic testing is a blood analysis to look for an extra chromosome. Down syndrome is a disorder caused by an extra chromosome 21. However, a chromosome test will not pick up a genetic disease caused by a single gene change, like cystic fibrosis.

Fluorescence in situ hybridization (FISH) Testing: Fluorescence in situ hybridization, also called FISH, is a technique that uses a specific protein, called a probe, that has been designed to "stick" to unique DNA in a cell. These probes are fluorescent, meaning they glow with a special dye. Laboratory personnel can then examine the cells under a microscope. FISH is currently used to detect the common chromosome problems caused by an extra chromosome (aneuploidy), such as Down syndrome (trisomy 21), and in prenatal diagnosis when results are needed rapidly. FISH can also be used to detect subtle chromosome rearrangements, identify marker chromosomes (extra pieces of unidentified chromosomal material), and test for common syndromes caused by duplication or deletions of large pieces of DNA.³

Pregnancy management decisions and diagnosis of problems should not rely on FISH alone, but should also take into account results of the full chromosome analysis and clinical findings.⁴

Biochemical Testing: Genes make proteins and enzymes that are present in blood or other tissues.² Proteins and enzymes carry out the work of the body, such as digesting fat or making energy available to muscle. Biochemical testing measures the level of protein or enzyme present in a patient's sample to help determine if the gene that produces that protein is functioning properly.⁵

An example of a biochemical test is enzyme analysis for Tay-Sachs disease. Tay-Sachs disease is an inherited disorder that causes neurological deficits, developmental delay, and death by age 4. It is caused by the lack of an enzyme called hexoseaminidase A (hex A). By measuring levels of hex A in the blood, it can be determined if a person is affected by Tay-Sachs disease or is a carrier.

Indirect (linkage) Testing: Not all of the genes have been located yet. For some genes, scientists know approximately where the gene is on a chromosome, but not exactly. This is like knowing the street someone lives on but not knowing the address. Indirect testing requires blood from several family members, including those that are known to be carriers or affected with a specific condition. Laboratories then compare genetic material between family members and determine who is most likely to be a carrier or affected.¹

In some families with hemophilia A, a genetic disorder resulting in excessive bleeding after injury or surgery, the gene mutation causing the disease cannot be identified with common laboratory test methods. Because DNA contains pieces, called markers, that are unique to individuals and families, laboratories can find the markers unique to a hemophilia family near the hemophilia gene. The markers from at least two affected family members are compared to the marker in the family member in whom the diagnosis or carrier status is being questioned. If the unique sequences from an affected family member are present in the person being tested, that individual is predicted to be affected or a carrier. Linkage can also be done for prenatal diagnosis.⁶

Direct Testing: Direct gene testing can be performed when scientists know exactly where a gene is located on a chromosome and what changes in the gene cause a specific disease. When they know this information, the scientists can look for the disease-causing gene changes in a person who is either suspected of having a genetic disease, or who may be a carrier for the disease.⁵

An example of direct testing is mutation analysis for cystic fibrosis. Cystic fibrosis (CF) is an inherited disease that causes lung and digestive problems. Common mutations (gene changes) in the cystic fibrosis gene have been identified. The American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG) recommend that CF carrier screening be offered to all couples when at least one member of the couple is Caucasian and pregnant or considering pregnancy.⁷ Carrier screening consists of direct detection for the 25 most common CF mutations. It is further recommended by ACOG and ACMG that CF screening be made available to individuals of other racial and ethnic groups.⁷

References

1. Thompson MW, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. 5th ed. Philadelphia, Pa: W.B. Saunders Company; 1991.
2. Milunsky, A. Heredity and Your Family's Health. Baltimore, MD. The Johns Hopkins University Press. 1992
3. The American College of Obstetricians and Gynecologists. Fluorescence In Situ Hybridization. Genetics in Obstetrics and Gynecology. ACOG; Washington, DC: 2002.
4. American College of Medical Genetics. Technical and Clinical Assessment of Fluorescence In Situ Hybridization: policy statement. Gen in Med 2000;2(6):356-361
5. Harper PS. Practical Genetic Counseling. Oxford, England; Butterworth-Heinemann Ltd; 1994:102.
6. Johnson MJ, Thompson AR. Hemophilia A. www.genetests.org. [Cited January 28, 2004].
7. American College of Obstetricians and Gynecologists, American College of Medical Genetics. Preconception and Prenatal Carrier Screening for Cystic Fibrosis: Clinical and Laboratory Guidelines. Washington, DC: ACOG; Oct 2001

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Are genetic tests always accurate?
Genetic tests have varying degrees of clinical accuracy.¹ For example, some tests are diagnostic, which means they can be used to tell if a person has or will develop a genetic problem. Other tests are pre-symptomatic (also called predisposition testing) or screening tests. Screening tests do not diagnose a specific disease; they only identify a person who is at an increased or decreased risk for developing that disease.

1. Harper PS. Practical Genetic Counseling. Oxford, England; Butterworth-Heinemann Ltd; 1994:102.

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Why would a physician offer genetic testing?
There are several reasons why a genetic test may be offered:

Carrier Screening

Carrier screening is the most common type of genetic testing performed today.¹ There are several common disorders where either one parent or both parents must be carriers of a certain gene or mutation to have an affected child, such as cystic fibrosis. In these circumstances, the carrier has no symptoms of the disease, but may have a baby with the disease if the other parent is also a carrier. It has become a standard medical practice to offer couples who are expecting a baby or planning a pregnancy screening for some of these diseases, most of which are listed on the Common Disorders page. Some types of carrier screening are not definitive; negative genetic test results mean the likelihood that a person is a carrier is reduced, but cannot entirely eliminate the possibility.

It is important to note that carrier screening is not recommended for minors.²

Diagnostic Testing

Diagnostic testing may be offered to a person when a physician suspects that the patient has a specific genetic disease. For example, if a patient has the symptoms associated with a specific genetic disease, the physician may choose to offer a genetic test to definitively diagnose or rule out that specific disease.

Prenatal Screening

Some tests are available that can screen for certain types of birth defects in a baby before it is born. This type of testing performed during a pregnancy cannot diagnose birth defects, it can only determine if a fetus is at increased risk for certain genetic disorders.⁴ If the fetus is identified to be at an increased risk, the parents may be offered additional testing.⁵

Maternal serum screening is an example of prenatal screening. AFP X-tra is a maternal serum screening test that identifies pregnancies at increased risk for open neural tube defects, Down syndrome, and trisomy 18. The blood test is a screening test and does not provide a definitive diagnosis.

Prenatal Diagnostic Testing

Prenatal diagnostic testing is available during a pregnancy to determine if a baby has a specific disease. The results of this type of testing are conclusive enough to diagnose or rule out a genetic condition before the baby is born. Testing is usually performed on amniotic fluid or chorionic villi samples.⁴

Amniocentesis is an example of prenatal diagnosis. In this test, a small amount of amniotic fluid (fluid surrounding the developing baby during pregnancy) is withdrawn. Cells from the baby are found in the fluid and the chromosomes in the cells can be examined. If, for example, an extra chromosome 21 is seen, a diagnosis of Down syndrome is made.⁴

Pre-implantation Diagnostic Testing

Testing is available for a limited number of genetic disorders on a single cell of an embryo from a procedure called in vitro fertilization. In vitro fertilization is the fertilization of the egg outside the womb in a laboratory. Certain genetic tests may be performed on a single cell removed from an embryo. After testing, selected embryos may then be implanted in the womb. This testing is only available at specialized centers, and may be considered experimental.⁶

References

1. Harper PS. Practical Genetic Counseling. Oxford, England; Butterworth-Heinemann Ltd; 1994:102.
2. The American Society of Human Genetics Board of Directors and The American College of Medical Genetics Board of Directors. Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents. Bethesda, Md: ASHG;1995.
3. Task Force on Genetic Testing. Interim Principles of the Task Force on Genetic Testing of the NIH-DOE Working group on Ethical, Legal, and Social Implications of Human Genome Research. Baltimore, Md: March 1996.
4. Thompson MW, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. 5th ed. Philadelphia, Pa: W.B. Saunders Company; 1991.
5. American College of Obstetricians and Gynecologists. ACOG Education Bulletin: Maternal Serum Screening. Washington, DC. September 1996(228).
6. Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. 6th ed. Philadelphia, Pa: W.B. Sounders Company, 2001.

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What other things should I be aware of when considering genetic testing?
To prepare for genetic testing, it is recommended that a patient consider consulting a genetic counselor or a physician who specializes in genetics to discuss the issues involved. There are several common concerns a patient may want to think about and discuss with his or her physician and counselor before having genetic testing:¹

• Genetic testing is often complicated. Occasionally the test does not succeed as desired, and more blood or tissue might be needed. Sometimes blood samples from other family members are needed to interpret a particular result.
• When multiple family members are tested, information about the relationships of family members could be revealed, such as adoption and non-paternity. However, most laboratories do not disclose this information unless it is a necessary part of the test result or interpretation.
• Genetic testing labs give special handling to patient specimens. Specimens are given a unique identifying number. The specimens and related information are kept in a secure place to maintain patient confidentiality. If any specimen remains after testing, it may be kept for up to 10 years for quality assurance purposes. If the patient does not want his or her specimen stored after testing, he or she can request that it be destroyed when testing is completed. If a patient wishes to have DNA permanently stored for his or her own future use, companies specializing in DNA banking are available.
• With a patient's permission, laboratories may use a specimen for research or quality control in their facility. Before this is done, the patient's name and all other identifying information are removed from the specimen so it cannot be connected to the patient. Ownership of the sample and any results from it become the property of the laboratory. Patients will not receive any results that come from their specimen as a result of research or quality control testing.
• Because genetic testing looks for inherited genetic conditions, patients are not only getting genetic information about themselves, but also their family. In some circumstances it is important to share test results with family members.
• Genetic testing may be expensive. Many patients prefer to check with their health care providers and insurance companies to ensure that insurance will cover the cost of testing. In some instances, patients may be required to pay for some or all genetic testing not deemed medically necessary or not offered as a covered benefit under their specific insurance plans.
• Genetic testing results may have an impact on major life decisions.
• In some cases, certain types of genetic tests may limit an individual's ability to obtain health, life, or disability insurance.

References:

1. Task Force on Genetic Testing. Interim Principles of the Task Force on Genetic Testing of the NIH-DOE Working group on Ethical, Legal, and Social Implications of Human Genome Research. Baltimore, MD: March 1996.