Genetic testing and counseling

Genetic testing examines the genetic information contained inside a person'scells to determine if that person has or will develop a certain disease or could pass a disease to his or her offspring.

A variety of laboratory techniques is used to examine genes or markers near genes. Direct analysis of an individual's specific genes can determine if theindividual suffers from diseases such as cystic fibrosis and sickle cell anemia. Indirect testing has to be done for certain diseases because the gene hasnot been directly identified, but are known to lie in a specific region of achromosome.

There are many types of genetic testing:

  • Carrier Identification includes genetic tests used by couples whose families have a history of recessive genetic disorders and are considering having children. Three common tests include those for cystic fibrosis, Tay-Sachs disease, and sickle cell anemia.
  • Prenatal diagnosis is genetic testing of the fetal cells from the mother's womb. This may be done when there is a risk that they mother may be carrying a child with genes associated with diseases that could cause some physicalabnormality or mental retardation. Down's Syndrome is one of the most commondiseases screened by this method.
  • Newborn Screening is frequently done as a preventative health measure. Tests usually have clear benefits to thenewborn because treatment is available. Phenylketonuria and congenital hypothyroidism are conditions for which testing is conducted in all 52 states.
  • Late-onset disorders include adult disorders such as cancer and heart disease. Genetic diseases may indicate a susceptibility or predisposition for these diseases. Diseases such as Huntington's disease which are seen only later in life are caused by single genes.

The human cell (except the egg cells, sperm cells and some blood cells, whichhave no nuclei) contain 6 feet of DNA molecules tightly coiled and packed into 46 chromosomes. This DNA has more than 3 billion base pairs and is the genetic blue print for each individual. The sequence of the four bases (namely the A, C, G, and T bases) on a DNA strand contains the recipes that encodes different proteins. These proteins carry out all body functions. They keep thehormonal balance in the body, help us maintain body temperature, determine how efficiently we process foods, how effectively we detoxify poisons, how vigorously we respond to infections and so on. If the recipes for the different proteins that are required by the cells have extra bases or misspelled bases or if some are deleted, the genes cannot make the right protein in the right amount. These mistakes often lead to diseases. It is now estimated that 3000 -4000 hereditary diseases are caused by some type of abnormality in our genes.

An alteration in the sequence of base pairs of a gene is known as a mutation.Gene mutations can be either inherited from a parent or acquired. A hereditary mutation is a mistake that is present in the DNA of all body cells. Hereditary mutations are called germline mutations because the gene change exists in the reproductive cells (germ cells) and can be passed from generation to generation. This mutation is copied every time the cells divide.

Acquired mutations also known, as somatic mutations are changes in DNA that develop during the life of a person. These could be due to the environment such as exposure to radiation or chemicals known as mutagens that have the ability to cause changes in the DNA. These mutations are passed on only to the direct descendants of those particular cells and not to all body cells, as is the case with germline mutations.

Mutations occur all the time in every cell of the body. However, each cell has a remarkable ability to recognize the mistakes and fix them before it is passed along to its descendants. Sometimes, however, the repair mechanism of the cells can fail or be overwhelmed, or become less efficient with age. Over time mistakes can accumulate in the DNA of the cells and alter the genes so much that it interferes with the protein production.

Genes come in pairs, with one copy inherited from each parent. Many genes come in a number of variant forms known as alleles. There are dominant alleles and recessive alleles. A dominant allele prevails over a recessive allele. Therefore, of the two copies of genes that each individual inherits, only one copy is actually performing the necessary function. A recessive allele of a gene becomes apparent only if its counterpart allele on the other chromosome becomes inactivated or lost.

For example, in cystic fibrosis, the gene that causes abnormal mucus production and the disease is a recessive allele. A person who inherits one copy of the recessive allele does not develop the disease because the normal allele predominates. However, such a person is a "carrier". A carrier is a person whois not affected by the mutated gene he or she possesses, but can pass the gene to an offspring. A carrier has a 50 - 50 chance of passing the altered recessive allele to each of his or her children. When both parents are carriers,the chance that a child will inherit two of the recessive alleles (one from each parent) and develop the disease is one in four (25%).

Genetic tests have been developed that tell prospective parents whether or not they are carriers of certain diseases. If one or both of the parents is 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 carriedon 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 (or female) 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.

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 onlyone 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 mutatedgene, 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 butnot affected; and a 25% chance of inheriting two normal genes. When only oneprospective 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% chanceof inheriting two normal genes.

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, like Huntington's disease, has been identified, a person from an affected family can be tested before symptoms appear.

Some families or ethnic groups have a higher incidence of a certain disease than does the population as a whole. Before having a child, a couple from sucha family or ethnic group may want to know if their child would be at risk ofhaving that disease.

Early in pregnancy, the baby's cells can be studied for certain defects thatcould result in physical abnormalities or mental retardation. This testing ismost common when the mother is over the age of 35 or there is a family history of physical or mental abnormalities.

A genetic disease may be apparent when the child is born or may appear lateras the child develops. Genetic testing can help diagnose these diseases. Couples who are having difficulty conceiving a child or who have suffered multiple miscarriages may be tested to see if a genetic cause can be identified.

Huntington's disease is an example of a genetic disease that does not appearuntil adulthood. If this disease or another late-onset disease is in a person's family, genetic testing may be able to predict if that person will developthe disease.

Some genetic defects may make a person more susceptible to certain types of cancer. Testing for these defects can help predict a person's risk.

Flaws in the genes, (the genetic material) can increase a person's risk of developing complex disorders such as cancer and heart disease. These diseases develop from a combination of both genetic predisposition and environmental factors, including diet and lifestyle. Certain types of genetic tests help diagnose and predict and monitor the course of certain kinds of cancer, particularly leukemia and lymphoma.

Some genes, called tumor suppressor genes, produce proteins that protect thebody from cancer. If one of these genes develops a mutation, it cannot 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 andenvironmental factors are also involved in the development of cancer.

Many genetic diseases and syndromes are caused by structural chromosome abnormalities. To analyze a person's chromosomes, his or her cells are allowed togrow and multiply in the laboratory until they reach a certain stage of growth. The length of growing time varies with the type of cells. Cells from bloodand bone marrow take 1 - 2 days; fetal cells from amniotic fluid take 7 - 10days.

When the cells are ready, they are placed on a microscope slide using a technique to make them burst open, spreading their chromosomes. The slides are stained: the stain creates a banding pattern unique to each chromosome. Under amicroscope, the chromosomes are counted, identified, and analyzed based on their size, shape, and stained appearance.

Karyotypes of the chromosomes are prepared for further study and to documentthe results. First, a photograph is taken of the chromosomes from one or morecells as seen through the microscope. Then the chromosomes are cut out and arranged side-by-side with their partner in ascending numerical order, from largest to smallest. The karyotype is done either manually or using a computerattached to the microscope. Chromosome analysis is also called cytogenetics.

Certain cancers, particularly leukemia and lymphoma is associated with changes in chromosomes: extra or missing complete chromosomes, extra or missing portions of chromosomes or exchanges of material (called translocations) betweenchromosomes. Studies show that the locations of the chromosome breaks are atlocations 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 thephysician information as to the effectivenessFor example, in cystic fibrosis,the gene that causes abnormal mucus production and the disease is a recessive allele. A person who inherits one copy of the recessive allele does not develop the disease because the normal allele predominates. However, such a person is 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. A carrier hasa 50 - 50 chance of passing the altered recessive allele to each of his or her children. When le takes only a few minutes.

Prenatal testing is done either on amniotic fluid or on a chorionic villus biopsy. To collect amniotic fluid, a physician performs a procedure called amniocentesis. An ultrasound is done to find the baby's position and an area filled with amniotic fluid. The physician inserts a needle through the woman's skin and the wall of her uterus and withdraws 5 - 10 mL of amniotic fluid. Placental tissue for a chorionic villus biopsy is taken through the cervix. Eachprocedure takes approximately 30 minutes.

Bone marrow is used for chromosome analysis in a person with leukemia or lymphoma. The person is given local anesthesia. Then the physician insertsa needle through the skin and into the bone (usually the sternum or hip bone). One-half to 2 mL of bone marrow is withdrawn. This procedure takes approximately 30 minutes.

Chromosome analysis is done on fetal cells primarily when the mother is overthe age of 35, has had multiple miscarriages, or a family history of a genetic abnormality. Prenatal testing is done on the fetal cells in amniotic fluid(the fluid surrounding the baby) at 14 - 16 weeks of pregnancy or from a chorionic villus sampling (from the baby's placenta) at 8 -12 weeks. Cells from amniotic fluid grow for 7 - 10 days before they are ready to be analyzed. Biopsy cells grow faster and can be analyzed sooner.

Chromosome analysis using blood cells is done on a child who is born with orlater 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 causes mental and physical abnormalities. A child born with an extra chromosome 21 (trisomy 21) has Down syndrome. Extra chromosomes 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. Afragile-looking area at the bottom of the X chromosome recognizes the abnormality.

Chromosome material may also be rearranged, such as the end of chromosome 1 moved to the end of chromosome 3. If no material is added or deleted in the exchange, the person may not be affected. Such an exchange, however, can causeinfertility 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 structural rearrangement. Many chromosome abnormalities are incompatible with life; babies with theseabnormalities often miscarry 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.

The cost of genetic tests varies: chromosome studies can cost hundreds of dollars and certain gene studies thousands. Insurance coverage also varies withthe company and the policy. It may take several days or weeks to complete a test.

Direct DNA mutation analysis examines DNA for specific gene mutations. Some genes contain more than 100,000 bases and a mutation of any one base can makethe gene nonfunctional and cause disease. The more mutations possible, the less likely it is for a test to detect all of them. This test is usually done on white blood cells from a person's blood. The test begins by using chemicalsto separate DNA from the rest of the cell. Next, the two strands of DNA areseparated by heating. Special enzymes (called restriction enzymes) are addedto the single strands of DNA, then act like scissors, and cut the strands inspecific places. The DNA fragments are then sorted by size through a processcalled electrophoresis. A special piece of DNA, called a probe, is added to the fragments. The probe is designed to bind to specific mutated portions of the gene. When bound to the probe, the mutated portions appear on x-ray film with a distinct banding pattern.

A technique called "linkage analysis" is used for indirect tests, and requires additional DNA from a family member of the affected individual for comparison.

Family linkage studies are done to study a disease when a mutated gene's general location on a chromosome is known but its identity is not. These studiesare possible when a chromosome marker has been found associated with a disease. Chromosomes contain certain regions that vary in appearance between individuals. These regions are called polymorphisms. If a polymorphism is always present in family members with the same genetic disease, and absent in family members without the disease, it is likely that the gene responsible for the disease is near that polymorphism. The gene mutation can be indirectly detectedin family members by looking for the polymorphism.

To look for the polymorphism, DNA is isolated from cells in the same way it is for direct DNA mutation analysis. A probe is added that will detect the large polymorphism on the chromosome. When bound to the probe, this region willappear on x-ray film with a distinct banding pattern. The pattern of bandingof a person being tested for the disease is compared to the pattern from a family member affected by the disease.

Linkage studies have disadvantages not found in direct DNA mutation analysis.These studies require multiple family members to participate in the testing.If important family members choose not to participate, the incomplete familyhistory may make testing other members useless. The indirect method of detecting a mutated gene also causes more opportunity for error.

Genetic testing is a complex process, and the results are dependent on reliable laboratory procedures and accurate interpretation of results. The tests also vary in their sensitivity, making interpretation of the test a very complex process even for trained healthcare professionals.

Genetic counseling aims to facilitate the exchange of information regarding aperson's genetic legacy. It attempts to:

  • Accurately diagnose a disorder
  • Assess the risk of recurrence in the concerned family members andtheir relatives
  • Provide alternatives for decision-making
  • Provide support groups that will help family members cope with the recurrence ofa disorder.

With approximately 2,000 genes identified and approximately 5,000 disorders caused by genetic defects, genetic counseling is important in the medical discipline of obstetrics. Genetic counselors, educated in the medical and the psychosocial aspects of genetic diseases, convey complex information to help people make life decisions. There are limitations to the power of genetic counseling, though, since many of the diseases that have been shown to have a genetic basis currently offer no cure (for example, Down syndrome or Huntington'sdisease). Although a genetic counselor cannot predict the future unequivocally, he or she can discuss the occurrence of a disease in terms of probability.

A genetic counselor, with the aid of the patient or family, creates a detailed family pedigree that includes the incidence of disease in first-degree (parents, siblings, and children) and second-degree (aunts, uncles, and grandparents) relatives. Before or after this pedigree is completed, certain genetic tests are performed using DNA analysis, x ray, ultrasound, urine analysis, skin biopsy, and physical evaluation. For a pregnant woman, prenatal diagnosis can be made using amniocentesis or chorionic villus sampling.

An important aspect of the genetic counseling session is the compilation of afamily pedigree or medical history. To accurately assess the risk of inherited diseases, information on three generations, including health status and/orcause of death is usually needed. If the family history is complicated information from more distant relatives may be helpful, and medical records may berequested for any family members who have had a genetic disorder. Through anexamination of the family history, a counselor may be able to discuss the probability of future occurrence of genetic disorders. In all cases, the counselor provides information in a non-directive way that leaves the decision-making up to the client.

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