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Genetic Testing; Overview.

Today, there are hundreds of different genetic tests, some of them for relatively common disorders, such as cystic fibrosis, and some for very rare diseases. A genetic test is fundamentally different from other kinds of diagnostic tests you might take. Indeed, a whole new field, genetic counseling, has grown up around the need to help patients understand the testing process.

The purposes of genetic tests vary. Some tests are used to confirm a preliminary diagnosis based on symptoms. But other genetic tests measure your risk of developing a disease, even if you are healthy now (presymptomatic testing), or whether you and your partner are at risk of having a child with a genetic disorder (carrier screening).

As the name suggests, a genetic test looks at your genes, which consist of DNA (deoxyribonucleic acid). Each gene contains a chemical message to produce a protein, which has a specific function in the body. Proteins are essential to life-they serve as building blocks for cells and tissues; they produce energy and act as messengers to make your body function. In addition to studying genes, genetic testing in a broader sense includes biochemical tests for the presence or absence of key proteins that signal aberrant gene function.

Some tests look at chromosomes for abnormalities such as an extra chromosome, or an incomplete or missing chromosome. Sometimes, pieces of chromosomes become switched, or transposed, so that a gene ends up in a location where it is permanently and inappropriately turned on or off. Chromosomes are made up of DNA with long chains of genes mixed with inactive DNA. Each of us has 46 chromosomes in the nucleus of each cell, half contributed by each parent. The genes on the chromosomes are responsible for directing our biological development and the activity of about 100 trillion cells in our bodies.

If something goes wrong with an essential protein, the consequences can be severe. For example, a protein called alpha-1 antitrypsin (AAT) clears the lungs of a caustic agent called neutrophil elastase. Those who cannot manufacture AAT because of a defect in the gene that produces the protein often develop emphysema and other complications.

Most genetic conditions come in the form of a mutation in a gene that alters the instructions for making the proteins. These mutations can lead to diseases ranging from those we think of as "genetic diseases," such as cystic fibrosis or AAT deficiency, to those we think of as degenerative diseases, such as cancer and heart disease. In the case of diseases like cancer, heart disease, asthma or diabetes, a combination of factors-some genetic, some related to environmental or lifestyle factors-may work together to trigger the disease.

It's possible to have a mutation, even one for a severe disease, such as cystic fibrosis (CF) and never even know it. That's because genes come in pairs-one contributed by your mother, one from your father. If you have a single such mutation, you are a healthy carrier of the disorder. Such disorders are called autosomal recessive. The unaltered gene in the pair retains the function. The disease becomes a possibility only if two carriers of the same recessive gene have a child. Each child of two carriers of the same disorder has a 25 percent chance of inheriting the disease. It is equally likely (a 25 percent chance) that both parents will contribute their unaltered genes, only the mutated genes, thus there is a 50 percent chance that the child will receive one functioning gene and one mutated gene-in other words, a 50 percent chance that the child will be a healthy carrier like the parents.

Some disorders, such as Huntington disease, are autosomal dominant. If a person has one mutated gene, its effects will cause the disease, even if the matching gene is normal. Thus, each child of a parent with Huntington disease has a 50 percent chance of inheriting the disease. Osteogenesis imperfecta, which causes brittle bones, is another example of a dominant disorder.

Autosomal means the gene is not found on one of the two sex chromosomes, X and Y. If each parent contributes an X chromosome, the child is a girl; an X and a Y chromosome makes the child a boy. Because girls have two copies of every sex-linked gene, they are less likely to have symptoms from X-linked genetic diseases than boys, who don't have a backup copy if an X-chromosome gene is mutated. Examples of X-linked diseases include forms of hemophilia and fragile X syndrome (the most common inherited cause of mental impairment).

Sometimes a genetic defect simply increases risk of developing a disease, often in conjunction with other genetic or environmental factors. For example, a mutation in a BRCA gene increases your risk of breast or ovarian cancer, but only if the companion unmutated copy of the gene in the same cell also acquires a mutation.

A normal copy of BRCA in a breast cell might acquire a mutation due to exposure to, say, an environmental toxin or radiation, or it might become mutated through a sporadic "mistake" during cell division and DNA replication. For a woman without a mutation, it would take two such events in one cell to trigger a BRCA-related breast cancer; for the woman who inherits a BRCA mutation, it takes only one. Other genes can also play a role. A woman with a BRCA mutation who also has a p53 (tumor suppressor gene) mutation would also be more vulnerable, and no doubt there are other genes whose malfunctioning in combination with a BRCA mutation can trigger breast cancer.

There also are other risk factors for breast cancer, such as high alcohol intake (more than two drinks per day), being overweight, not having children or having an early onset of menses.

Most women who develop breast cancer have no known risks for developing the disease other than being a woman or, in the case of an older woman, age. Age is a risk factor for developing many types of cancer.

An increased risk does not necessarily mean you have a disease or will develop it. Genetic test results can yield information to help you and your health care professionals better manage your health, or, in the case of prenatal testing, your baby's care.

Unfortunately, though, genetic tests do not always provide the clear answers you may want. Sometimes a mutation is found that is of uncertain significance. Also, many tests are designed to look for the most common disease-causing mutations. If you or your family has a unique mutation, these tests won't pick it up. Hence, many of the tests boast detection rates of 95 percent or more, but they are not perfect. If you have a strong family history of a disease and uncertain or negative test results, it may be better to play it safe and take added prevention measures as if you had tested positive for the mutation. A genetic counselor can provide guidance.

The Cost of Genetic Testing

The cost of a genetic test varies dramatically, ranging from about $50 to upwards of $2,000. The difference stems largely from the variation in labor intensity of different tests. Some tests look for a limited number of mutations (sometimes only one) known to cause a disease; others require sequencing of the entire gene. It's the difference between looking at a few particular frames of a film for defects and examining the entire reel.

The explosion of genetic research now taking place is expected to bring prices down and dramatically increase the number of tests available. In the coming years, tests may be available to predict your genetic risk of developing heart disease or diabetes, for example, and will help you and your health care professional develop specific strategies for prevention. Preventive efforts can include changing your lifestyle or perhaps taking certain medications, which may be tailored to your specific genetic profile, and early screening to head off the worst complications should you develop the disease.

What is Genetic Counseling?

Because the nature of genetic testing is so complex, with implications for both the person being tested and his or her family, counseling is desirable before taking any genetic test and essential if results come back positive or uncertain. Unlike most medical appointments, a counseling session may be a family affair, with participation of all concerned relatives. Counselors say sometimes a dozen or more relatives attend.

A genetic counselor is a health care professional who is an expert in counseling, genetics and genetic testing. She (most today are women) reviews your family history to determine if there appears to be a hereditary pattern of disease and who might be affected. A genetic counseling session usually lasts at least an hour and includes:

* gathering background information on your family and the disease under discussion

* providing information on inheritance, the genetic testing procedure, the possible results and what they mean

Testing usually is not performed at the first counseling session, and there is never any pressure to take a test. Genetic counseling will educate you so you can make an informed decision. If you are feeling ambivalent, counseling won't push you in one direction or the other, but it can help you decide whether testing is right for you.

Because family history is so crucial to deciding whether testing has a chance of identifying a disease-linked mutation, a counselor may request medical records to confirm a diagnosis, especially if you're trying to determine whether a family pattern of cancer is hereditary.

Family member recollections can be inaccurate-who had which disease or even what type of disease. Many conditions either were not discussed or not diagnosed in past decades. A genetic counselor will listen to a family account and help tease out details to better identify potential patterns.

Many women never think about genetic testing until they are considering having a child or have become pregnant. Prenatal testing offers an opportunity to test for chromosomal and common genetic disorders, as well as genetic conditions that have surfaced on either side of the family or for which either parent is a carrier. Counselors recommend a preconception session to discuss carrier testing and prenatal testing options.

Privacy Concerns

Genetic counselors are committed to protecting your privacy. They will not contact other family members without your permission, though they may encourage you to share results that might affect your relatives. Many counseling centers will store records of test results separate from your main medical record to help keep the information out of the hands of insurers and employers, unless you give permission to share. (Of course, if you use insurance to pay for testing, the company will have access to your file.) If you are concerned about your privacy, ask your genetic counselor about the center's policy. Thus far, experts say, there has been little evidence of insurer or employer discrimination based on genetic testing, but that may change once such testing becomes commonplace.

How to Find a Counselor

You can find a genetic counselor at, the Web site for the National Society of Genetic Counselors. The core credentials are a master's degree in the field and certification conferring the designation of certified genetic counselor (CGC).

Genetic Testing And Children

Up to age 18, genetic tests are used only for diagnosing conditions for which the proper care during childhood or adolescence can make a difference, not for doing carrier screening or testing for diseases that may affect children later in life (presymptomatic testing).

Newborn screening programs are now widely available for genetic diseases treatable early in life. Such a test can indicate elevated risk of a disorder, and a positive result should be followed up with further diagnostics. Below are the most commonly administered newborn screening tests, though remember that not every state administers every test (check with a health care professional to find out):

Phenylketonuria (PKU) is characterized by an inability to metabolize an amino acid called phenylalanine and causes mental retardation unless a specialized phenylalanine-free diet is put in place. Aspartame (Equal) should be avoided if you have PKU.

* Hypothyroidism can interfere with growth and mental development if not treated.

* Galactosemia can cause mental retardation if not treated with a diet free of a sugar called galactose, which is found in dairy products.

* Sickle cell disease makes a baby more susceptible to infection but early treatment with penicillin reduces the risk.

Newborn screening programs designed to test for 30 conditions are now being introduced in some hospitals. If this type of program is not available at your hospital, you can obtain your own kit by mail and have your baby tested at the hospital or your pediatrician's office. One source is Neo Gen.

Prenatal Testing

Prenatal testing to detect chromosomal defects and inherited genetic disorders has been widely available for women with high-risk pregnancies since the 1970s. These days nearly every pregnant woman in the U.S. has a preliminary maternal serum screening test performed.

The serum test, a simple blood test, is usually performed between week 15 and week 18 of the pregnancy (as measured from the start of the most recent menstrual period). The test evaluates your risk of having a baby with:

* An open neural tube defect. When the neural tube fails to close, the baby is born with an opening in the head (anencephaly) or spinal cord (spina bifida). Babies with anencephaly are stillborn or die soon after birth; those with spina bifida need surgery and may be paralyzed.

* Down syndrome (also called Trisomy 21). An extra copy of chromosome 21 causes Down syndrome, characterized by mental retardation, certain facial features and sometimes heart defects.

* Trisomy 18. An extra copy of chromosome 18 causes this syndrome, which usually proves fatal during the first year of the baby's life and is associated with severe mental retardation.

The blood screen does not look directly at genetic material but instead measures three substances-alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin-to determine whether you are at increased risk of having a baby with one of these disorders. A key fact to remember is that this test does not diagnose the disorders-it only screens for the substances. Further testing is always suggested to make a diagnosis.

Indeed, most of the time, the fetus is not affected with the disorder even if the screening result is abnormal. According to Genzyme Genetics, a genetics laboratory based in Framingham, Mass, out of 1,000 serum screening tests, 25 will suggest an increased risk for open neural tube defects, but only one or two of the fetuses will have such a defect. Likewise 70 out of 1,000 will test positive for increased risk of Down syndrome, but only one or two fetuses will actually have the condition.

Most labs offer the standard "triple marker" serum screening test, which picks up about 70 percent of Down syndrome cases among women under 35, and 85 to 90 percent in women 35 and older. A recently introduced four-marker test incorporating a measure for a chemical called inhibin-A improves detection rates for Down syndrome by five to 10 percentage points. Some centers also offer first trimester screening to determine if a woman is at increased risk for having a baby with Down syndrome or trisomy 18. The test has two parts and both should both be performed between the 10th and 13 weeks of gestation. One part tests levels of maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in the mother's blood. The other measures the nuchal thickening (measure of fetal neck thickness) through a specialized ultrasound. This test detects more than 90 percent of fetuses with Down syndrome and approximately 97 percent with Trisomy 18. However, it is a screening test and still requires a confirmatory chorionic villous sampling or amniocentesis to make the definite diagnosis.

A screening test does not diagnose a problem. It should not be used to make either treatment decisions or decisions to terminate a pregnancy, but rather should be used to determine appropriate next steps.

Diagnostic Follow-Up In Prenatal Testing

If a screening test indicates a higher-than-average risk, your health care professional may want to perform a basic ultrasound, which can help determine the gestational age of the fetus and show if a woman is carrying twins. If either of these factors accounts for the abnormal triple screen test result, no further testing is needed. Otherwise, a more detailed ultrasound examination may be performed, which allows a look at the baby's brain and spinal cord, as well as other parts of the body. This ultrasound can often identify an open neural tube defect or other malformation associated with an abnormal screening test.

Your health care provider may suggest you consider either amniocentesis or chorionic villus sampling (CVS). Both are diagnostic tests to determine whether the fetus actually has the disorder in question. Amniocentesis is performed more frequently and should be the choice if you're at risk having a child with neural tube defects.

If you have amniocentesis, a doctor will use a needle to withdraw a sample of amniotic fluid (the fluid surrounding the fetus) for analysis. The procedure is typically performed during the second trimester, at 15 to 18 weeks.

Amniocentesis or CVS are also offered for high-risk pregnancies, which could be indicated by any of the following:

* you will be 35 or older at delivery

* your family has a known genetic disorder

* you have had a previous child with a birth defect

* you and your partner are carriers of the same recessive disorder

Both CVS and amniocentesis can cause cramping, and a small number of women have miscarriages following the procedures (the risk is higher with CVS, but still only about one percent).

CVS is an alternative to amniocentesis. The procedure is done at 10 to 12 weeks and involves analyzing a sample of placental tissue. A thin tube inserted through the vagina and cervix is used to suction out the tissue sample. However, unlike amniocentesis, CVS cannot be used to test for neural tube defects, such as spina bifida and anencephaly. Therefore, it's usually recommended that a woman undergoing CVS also have the prenatal blood test called the maternal serum alpha fetoprotein (MSAFP) screening test, at about 16 to 18 weeks of pregnancy. This test identifies most (but not all) pregnancies at risk for neural tube defects.

If you have a choice of amniocentesis or CVS, discuss the risks and benefits of each and the possible results with your doctor and, if possible, a genetic counselor.

CVS is more attractive to some women because it can be done much earlier, at 10 weeks to 12 weeks. Many women say that this is a time when pregnancy is still a private issue. But other women feel the slightly higher risk of CVS is unacceptable, and they wait for the amniocentesis.

Amniocentesis and CVS are used to diagnose many, but not all, genetic disorders prenatally. If a genetic disorder for which a test is available has surfaced on either side of the family, or if you and your partner are carriers for the same testable recessive disorder, your health care professional will probably suggest testing, to determine if the fetus has inherited the disease. If two parents are carriers for the same recessive disorder, each child has a 25 percent chance of being born with the disease.

Of course, the ideal time for many tests is before you get pregnant. If you are planning a pregnancy, preconception genetic counseling sessions can help determine what, if any, conditions may be in your genetic background that future children could inherit. Preconception screening offers an opportunity to make decisions without the pressure of an advancing pregnancy. You can also start to take folic acid (4 mg/day) before conception to reduce your risk of having a baby with a neural tube defect.

Handling The Results

No test guarantees a healthy baby. While amniocentesis and CVS are extremely accurate, they look only for evidence of specific genetic or chromosomal disorders and cannot take into account other factors, including sporadic genetic mutations (without a hereditary component), which may affect a child's development.

When an untreatable genetic disorder is diagnosed prenatally, parents have the option of continuing or terminating the pregnancy. A genetic counselor can help you learn more about the disorder and weigh your options in a neutral setting. The decision is a tough one, and parents may weigh such factors as whether the disorder can be treated, the family's ability to manage the disorder or disability, the extent to which an affected child will be disabled or in pain, and how long the child is likely to live.

Prenatal testing can be valuable if you opt to continue a pregnancy knowing the child will be born with a particular disease. The diagnosis often can help you, your family and your health care team better manage the pregnancy, the delivery and any treatment the newborn will need.

In rare cases, a disorder diagnosed prenatally can be treated before birth. For example, congenital adrenal hyperplasia, which causes genital abnormalities in girls, can be treated with hormones given to the mother. Some centers are also experimenting with in utero surgery to correct spina bifida. But such opportunities to correct birth defects are still very much the exception.

Carrier Screening

You could be carrying a genetic mutation for a debilitating disease such as cystic fibrosis, sickle cell disease or Tay-Sachs disease and not even know it. That's because carriers of these mutations have no symptoms-in fact, they don't even have the disease.

Genes come in matched pairs, except for those on the sex chromosomes. In the case of autosomal recessive disorders such as these, if only one of these matched genes is damaged, there's no problem. The unaffected gene does the job. In fact, a disease-causing mutation can run through dozens of generations of a family without ever making itself known.

But if two carriers of the same gene change have a child, their chance of passing on what genetic counselors sometimes call a "double whammy"-two defective genes-is 25 percent. Of course, their chance of passing on two unaffected genes is also 25 percent, and the chance that a child will be a healthy carrier (with one normal gene and one defective one, but not afflicted with the disease) is 50 percent.

The exception to this pattern occurs if a disorder is recessive and X-linked. The X is the symbol for the larger sex chromosome. A child who inherits two X chromosomes is a girl. A child with an X chromosome and a Y chromosome is a boy. If a mother has a disease-linked recessive mutation on one of her X chromosomes, she is a carrier of the disorder but should have no or minimal symptoms herself. If she has a son, he will have a 50 percent risk of inheriting the disorder because he has no backup X chromosome; a daughter will have a 50 percent chance of being a carrier, like her mother.

Fragile X syndrome, as its name suggests, is one such X-linked disorder. Boys who inherit the mutation usually develop the disease, the most common form of genetically inherited mental retardation. Girls who inherit a fragile X mutation are more likely to be carriers. (The gene is unstable and the mutation tends to increase in size over succeeding generations, so that girls may eventually be affected as well, though the mental retardation is not usually as severe as it is in boys.) All affected individuals are related through females, as the fragile X gene "grows" only in the egg. If you have a family history of mental retardation, testing can determine whether a fragile X mutation is responsible and whether you are a carrier.

As with other types of testing, genetic counseling can help you understand carrier screenings. A counselor can also help you develop strategies for sharing the information with other family members who may also be at risk of carrying the mutation.

Carrier screening is recommended for any disorder that has surfaced in your family, either by virtue of a relative developing the disease or testing positive as a carrier. However, you should also consider screening for mutations found frequently in your particular ethnic group. The prevalence of genetic disorders is linked closely to ethnic heritage. Caucasians, for example, have a much higher risk than most other groups for cystic fibrosis, and those of African American descent are more likely to be carriers of sickle cell anemia mutations.

Many carrier screening tests are relatively inexpensive (usually $50 to $75 per individual screen) because they don't require sequencing of an entire gene. Instead they zero in on mutations known to be common in particular groups. The results are generally very accurate (95 percent or higher) and straightforward: A person is either a carrier or not.

Below is a list linking various groups to genetic disorders they are more likely to inherit:

* Caucasians: phenylketonuria, hemochromatosis, cystic fibrosis, alpha 1-antitrypsin deficiency, celiac disease (no genetic test available, but physicians can test blood to measure levels of antibodies to gluten. These antibodies are antigliadin, anti-endomysium, and antireticulin.)

* African Americans: sickle cell disease and thalassemia

* East Asians (except Koreans): thalassemia

* Irish, French Canadians and Cajuns: Tay-Sachs disease

* Mediterraneans: thalassemia, celiac disease, and familial Mediterranean fever

* Southeast Asians (Cambodians, Laotians and Vietnamese): hemoglobinopathies (disorders of hemoglobin, the oxygen-carrying component of red blood cells)

There is also a battery of tests for mutations found more often in the Ashkenazi Jewish population. The Ashkenazi are Jews of Central and East European descent, and they account for some 80 percent of the Jewish population in the United States.

The carrier screening tests for Ashkenazi Jews varies from program to program. Some test only for Tay-Sachs and Canavan diseases; some include many other disorders, such as Gaucher disease, Bloom syndrome, Fanconi anemia, Niemann-Pick disease and hereditary deafness. If you use insurance to pay for testing, you may have to use a particular center and test panel. Testing for Familial Dysautonomia is now available, too.

Many panels also include a screen for cystic fibrosis (CF). This condition is not more common in the Ashkenazi population. Caucasians are actually more likely to carry CF mutations than other groups. Still, the ratio of the Ashkenazi population that carries known CF mutations is fairly high, about one in 29. Three specific mutations are common in this population, making testing more specific.

People of Ashkenazi Jewish origin are, of course, no more likely to have a genetic disorder than other populations; they have been the focus of much genetics research because the population remained relatively isolated and small for centuries.

Experts Recommend Preconception Screening

You might think that if you and your partner come from different backgrounds, carrier screening is unnecessary. The American College of Obstetricians and Gynecologists, however, advises that if one partner in a couple is at high risk and the other is not, the high-risk partner should be screened. If that person tests positive as a carrier the other partner should be screened.

Genetics experts recommend carrier screening in young adulthood or before a marriage-and definitely before a couple tries to conceive. But you may have to be proactive in seeking the testing. If you live in a region where there aren't many members of your ethnic group, a local physician may not be well informed about the issues.

If two prospective parents are found to be carriers of a disease, their options include:

* adoption

* use of donor sperm or a donor egg

* in vitro fertilization and preimplantation genetic testing of the embryos (an expensive process)

* prenatal testing (with the option of an abortion if the fetus has two copies of a debilitating mutation)

For some diseases, the outcome of having two mutated genes is variable from patient to patient. Someone with a particular disease mutation, for example, may not have symptoms until middle age, or may go a lifetime asymptomatic, making decisions about testing-and what to do if a fetus turns out to be affected-difficult for prospective parents.

Testing for Inherited Cancer

If you have a family history of cancer, particularly cancers that occur before age 50, you may want to explore genetic counseling to determine if an inherited gene mutation could be responsible. Hereditary cancers are not always obvious. A mutation that leads to breast cancer in your grandmother may lead to ovarian cancer in your aunt. Likewise, a mutation that causes colon cancer in your sister may cause endometrial cancer in your daughter.

To determine whether your family's cancers might be hereditary in nature, a genetic counselor will need to know medical details about the family, especially those who have been diagnosed with cancer. Age of diagnosis and the exact diagnosis are the most important factors; be prepared for a counselor to request medical records. Also be prepared for several possible conclusions about your family history:

* The cancers in the family, even if there are several, may be "sporadic" and not linked to an inherited genetic defect.

* The pattern fits a known hereditary cancer syndrome for which genetic testing is available. Those who test positive for the mutation would need to be vigilant about prevention and screening measures.

* Family history suggests an inherited pattern, but one that fits no currently characterized syndrome. Everyone who may have inherited the apparent predisposition to cancer should pursue stepped-up prevention and screening efforts.

Some inherited cancer syndromes for which testing is available are:

* Hereditary breast and ovarian cancer syndrome, caused by mutations in the BRCA1 or BRCA2 genes, often referred to as the "breast cancer genes."

* Hereditary non-polyposis colon cancer, caused by mutations in the MLH1 and MSH2, genes. Such mutations are also linked to cancers of the endometrium, stomach, small bowel, ureter, ovary and collecting system of the kidneys.

* Familial adenomatous polyposis, caused by a mutation in the APC gene that leads to the growth of hundreds or thousands of polyps in the colon beginning as early as the teenage years.

* Ataxia telangiectasia, a complex disorder caused by a mutation in the ATM gene. Among other effects, including dysfunction of the cerebellum (the part of the brain that controls motor function and balance), A-T has been linked to lymphomas and leukemia. This autosomal recessive disorder is diagnosed in childhood. As individuals live longer, other cancers have been observed, including ovarian and breast cancers, stomach cancer and melanoma.

* Multiple endocrine neoplasia 1 and 2 are two separate rare disorders caused by mutations in the MEN1 or RET genes, respectively; MEN1 or 2 can lead to cancer in one of the endocrine glands, such as the parathyroid, thyroid, pancreas, pituitary or adrenal gland.

* Researchers also suspect a hereditary component to some cases of prostate and lung cancer, but as yet have not identified gene mutations for testing.

The genes themselves don't cause cancer. The problem comes when they are not functioning normally. You were born with two copies of each of these genes, one inherited from your mother and one from your father. In some cases, if you inherit a mutation in one of these genes, you will not immediately develop cancer, because you have a backup functioning gene. But over time, the unaffected gene may become damaged in one cell, allowing that cell to become cancerous and multiply.

Such an outcome is common among individuals with an inherited mutation linked to breast cancer or colon cancer. Those with a BRCA mutation face a lifetime breast cancer risk of up to 85 percent, compared to about 12.5 percent in the general population, and a lifetime ovarian cancer risk of up to 44 percent, compared to a population risk of about one percent.

A positive result from a genetic test does not mean you will definitely develop one of these cancers, only that your risk is much higher than that of individuals without a mutation. And a negative test result certainly does not mean you won't develop cancer. In fact, only one out of 10 cases of breast cancer involves an inherited mutation, and only five to 10 percent of colon cancers are hereditary.

The knowledge that you are positive for a mutation allows you to take action to reduce your risk through preventive measures, such as more frequent screening to detect early growths or tumors, taking protective

medications, or even prophylactic surgery to remove the organ prone to cancer.

Breast Cancer Testing

Are You A Candidate For Breast Cancer Testing?

Because breast cancer is one of the most common cancers, the test women are most often asking about is the one for BRCA mutations. A Salt Lake City-based company called Myriad Genetics has patented the BRCA genes and performs genetic testing. The lab testing is complex, but all that is needed from you is a blood sample.

It is important to remember that even when a family has a mutation, not everyone will inherit it. You have two copies of every gene. If one of your father's two copies of, say, BRCA1, has a mutation, your chance of inheriting that mutation is 50 percent. Thus, in a group of siblings, some will inherit a mutation, others won't. If your sister has breast cancer and you don't, she's the better candidate for testing, because if you test negative for a mutation, it may mean there's no mutation in the family, or may simply mean you didn't happen to inherit it. The result gives no guidance for the rest of your family.

An initial comprehensive analysis of BRCA1 and BRCA2 costs $2,580; if a mutation is identified in the first person tested, subsequent tests for other family members are $295 each. The reason the first test is so expensive is that the genes must be fully sequenced to identify the mutation. Once a mutation is found, the technicians know where exactly to look in the other relatives' DNA samples. A variation of the test that looks only at three specific mutations found in the Ashkenazi Jewish population (Eastern European background) is $350.

If no one in your family has been diagnosed with breast or ovarian cancer, then your risk of carrying a BRCA1/2 mutation is very small and testing would not be recommended. Keep in mind, however, that absence of these mutations doesn't mean you won't develop cancer. At least 90 percent of breast and ovarian cancer cases are "sporadic," meaning they don't stem from inherited mutations, but rather are caused by a mutation, or combination of mutations that arise over time. Therefore, regardless of your genetic status, be sure to take precautions such as having a once-yearly breast examination by your health care professional (called a clinical breast examination) and a mammogram, if appropriate (schedule based on age).

You might be a candidate for BRCA testing if your family has:

* Two or more members with breast and/or ovarian cancer. Note that the evidence of a mutation is just as strong if your mother has breast cancer and your sister has ovarian cancer as it would be if both had breast cancer. And because ovarian cancer is much rarer than breast cancer, two such cases are even more suggestive of an inherited mutation.

* A relative whose cancer was diagnosed at a young age (under 50). Multiple incidences of early-onset breast or ovarian cancer are the No. 1 tip-off that a BRCA1/2 mutation might be lurking in the family. About three-fourths of breast cancers are diagnosed after menopause, so a younger age of onset serves as a good red flag.

* An incidence of breast and ovarian cancer in the same woman, or two separate primary breast cancers in the same woman.

Your ethnic background may come into play with breast cancer risk as well, if you are of Ashkenazi Jewish descent. Women with such a background are about 10 times more likely to have a mutation than women in the general population. If you are of Ashkenazi Jewish descent, you may also consider testing if one family member has been diagnosed with breast cancer before the age of 45. Testing looks for three specific mutations that account for 90 percent of the positive BRCA1/2 gene changes in this population. If the test comes up negative in the face of a strong family history, a comprehensive BRCA full-sequence analysis may be ordered.

As you think about your family history and any associated risk, be sure to look at your father's side, as well as your mother's. If women on his side of the family have a mutation, you face as much risk of inheriting it as you do of inheriting a maternal-side defect.

If you are not sure but think there's a possibility that your family has a hereditary cancer pattern, talk to a genetic counselor. Genetic testing for cancer predisposition is an individual choice for adults. Some women prefer not to get tested, and some young women prefer to wait.

Did You Test Positive?

If you test positive for a BRCA mutation, there are options for minimizing your cancer risk, but none of them reduce your risk to zero:

* Stepped-up screening and prevention efforts. If you test positive, mammography is recommended starting at age 25 and repeated annually. You should do a breast self-exam once a month, at the same time of the month. If you're premenopausal, you may want to do it the week after menstruation. A clinical breast exam by a physician is also recommended every six months (instead of the usual once a year).

* Chemoprevention, or taking medications to reduce your risk. Tamoxifen, a treatment for breast cancer, can cut breast cancer risk 50 percent in high-risk patients. Raloxifene, a similarly designed drug that is approved for preventing osteoporosis is also under study as a cancer-preventing agent. Oral contraceptives containing estrogen and progestin can cut ovarian cancer risk up to 60 percent.

* Prophylactic surgery to remove the breasts (mastectomy) and/or ovaries (oophorectomy). This is the most radical option, but some women choose it because of the high lifetime risk of cancer that accompanies BRCA1/2 mutations.

Oophorectomy is increasingly being recommended for women who test positive for BRCA mutations and are either finished with childbearing or are certain that they do not want children. Removal of the ovaries not only reduces ovarian cancer risk 90 to 95 percent, it also reduces breast cancer risk 50 percent. That's because the ovaries produce estrogen, which stimulates breast growth and is linked to cancer risk. The bad news is that removing the ovaries also removes your body's source of estrogen. Therefore, estrogen levels diminish rapidly and trigger menopausal symptoms, such as hot flashes, vaginal dryness and bone loss, among other short-term physical and emotional changes and long-term health risks associated with menopause. For some women, "surgical menopause," when one or more ovaries is removed, can trigger more sudden and severe menopausal symptoms than when menopause occurs spontaneously at the end of a woman's childbearing years-a transition that typically takes about five years in a woman's late 40s.

Postmenopausal hormone therapy (often referred to as hormone replacement therapy or HRT) can be prescribed prior to or just after surgery to mitigate menopausal symptoms. However, women, health care professionals, and the Federal government are scrutinizing the use of postmenopausal hormone therapy more closely than ever before and its safety for both long-term and short-term use is in question.

In January 2003, the U.S. Food and Drug Administration (FDA) announced that it would require a new, highlighted and boxed warning on all estrogen products for use by postmenopausal women. The so-called "black box" is the strongest step the FDA can take to warn consumers of potential risks from a medication. The warning highlights the increased risk for heart disease, heart attacks, stroke and breast cancer from supplemental estrogen-risks illuminated by part of the Women's Health Initiative study, which was abruptly halted in July 2002 when the risks were identified.

The "black-box" warning also advises health care professionals to prescribe estrogen products at the lowest dose and for the shortest possible length of time. Women taking estrogen products are cautioned to have yearly breast exams, perform monthly breast self-exams and receive periodic mammograms.

Because every woman's risk profile is different, women who are thinking about taking postmenopausal hormone therapy or are currently taking it for whatever reason, need to review their options and treatment plans with their health care professional in light of the FDA's recent warning.

New, lower-dose versions of the hormone therapies used to treat symptoms of menopause are currently being developed. The FDA recently approved a low-dose version of the combination estrogen-progestin treatment sold as Prempro, which is expected to be available in the summer of 2003.

Families with hereditary cancers may choose to participate in research studies and familial cancer registries. This option helps researchers identify new cancer-associated genes and ultimately may aid the design of better cancer therapies. Registries and research are typically housed at the nation's leading cancer centers, so participation can also provide better access to top-quality, cutting-edge care. Participants give informed consent and their privacy is protected.

Colon Cancer Testing

Are You A Candidate For Colon Cancer Testing?

If your family has a history of colorectal and related cancers, you may want to consider genetic testing for mutations in two genes strongly associated with a hereditary nonpolyposis colon cancer (HNPCC). The syndrome increases lifetime risk of colorectal cancer to 80 percent vs. a two percent population risk, but also boosts your risk of endometrial cancer (to 60 percent), ovarian cancer (to 12 percent) and gastric cancer (to 13 percent). Those with HNPCC also face a higher risk of cancers of the kidney and ureter, gallbladder, central nervous system and small bowel.

To determine whether testing might be appropriate for your family, a genetic counselor would look for incidence of these cancers in two or more family members at a young age (under 50), or incidence of two types of cancer in one family member at a young age. Testing is also an option if you have two first-degree relatives (parents, siblings or children) diagnosed with one of these cancers at any age.

Many aspects of the testing parallel BRCA testing. The ideal initial candidate is a person who has been diagnosed with cancer, and the initial test runs about $2,000 with subsequent tests for other family members costing about $300.

Preventive options for those who test positive include:

* Annual colonoscopies beginning in the early to mid-20s

* Annual screening for endometrial cancer using transvaginal ultrasound and/or endometrial aspirate beginning in the 20s

* Prophylactic surgery to remove the colon (rarely recommended), the uterus and/or the ovaries

Genetic counseling is vital at every step to help educate you to make the best choices for yourself and your family.

There are also tests available for mutations associated with a rarer colon cancer syndrome called familial adenomatous polyposis, which is typified by a very early age of onset (the teens) and appearance of many polyps.

About The Diseases

Alpha-1 antitrypsin (AAT) deficiency leads to lung damage and emphysema by the third or fourth decade of life. Liver disease may occur in the first few months of life. The condition is worsened by smoking. A replacement therapy is available but in chronically short supply, and it is not known how effective this is once disease has developed or which people would benefit most. You should consider carrier screening if you have a family history of the disease.

Celiac disease is the most common genetic disease in Europe affecting, for example, about one in 250 people in Italy and one in 300 in Ireland. In celiac disease, a protein called gluten (found in grains) provokes the body's immune system to destroy the small intestine's nutrient-absorbing villi. This destruction leads to malnourishment, but with a gluten-free diet, the villi heal. A gluten-free diet means avoiding all foods that contain wheat, rye, barley, and possibly oats--in other words, most grain, pasta, cereal and many processed foods. Despite these restrictions, people with celiac disease can eat a well-balanced diet with a variety of foods, including bread and pasta. For example, instead of wheat flour, people can use potato, rice, soy or bean flour. Or, they can buy gluten-free bread, pasta and other products from special food companies. The disease is believed to be underdiagnosed in the U.S., where the time between the first symptoms and diagnosis averages about 10 years. Children of a person with celiac disease have about a five to 10 percent chance of developing the disease. You may want to consider screening for yourself or a child if a close relative has celiac disease or symptoms such as anemia, delayed growth or weight loss appear. There is an increased incidence of celiac disease in individuals with Down syndrome.

Congenital adrenal hyperplasia (CAH) is caused by insufficient production of an essential chemical called cortisol. Children with CAH may have male features, such as excess facial hair, and tend to stop growing early and have trouble fighting infections and retaining salt. Girls with the severe form of the condition may have genital defects. The mild form has similar, but less pronounced, symptoms and may go undiagnosed. You may want to consider screening if you have a family history of the disease. During pregnancy, treating the mother can prevent the severe manifestations of CAH.

Cystic fibrosis is characterized by the production of thick mucus, leading to pulmonary and digestive problems. The disease is caused by a mutated CFTR gene (cystic fibrosis transmembrane regulator). About one in 25 Caucasian Americans is a carrier of a mutation in this gene. Cystic fibrosis occurs most frequently in Caucasians of northern European origin. Because there are many possible disease-causing mutations in the gene, most tests are only about 80 to 85 percent accurate and this may be lower in some ethnic groups. Tests for Ashkenazi Jewish carriers are 97 percent accurate, however, because there are three specific mutations in this population for this condition.

Fragile X syndrome is an X-linked recessive disorder that is the leading cause of genetically inherited mental retardation. Because the mutation (in a gene called FMR-1) is X-linked, boys are affected more frequently and more severely; often women are carriers with no or less severe symptoms, however, females can be affected. The mutation consists of segments of unstable DNA that are repeated; the repeats lengthen with each succeeding generation, leading to greater impairment in offspring. Consider carrier screening if you have a family history of Fragile X or mental retardation in male relatives.

Hemophilia A and B are X-linked recessive disorders characterized by low levels or absence of one of two essential blood-clotting proteins. About 20,000 males suffer from hemophilia, with hemophilia A accounting for 85 percent of cases. Treatment with the clotting proteins is expensive. Consider carrier testing if you have a family history of hemophilia or excessive bleeding.

The neurofibromatoses are genetic disorders of the nervous system that primarily affect the development and growth of neural (nerve) cell tissues. These disorders cause tumors to grow on nerves and produce other abnormalities such as skin changes and bone deformities. The neurofibromatoses occur in both sexes and in all races and ethnic groups. Scientists have classified the disorders as neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). Brown birthmarks known as "cafe-au-lait" marks are frequently the first sign noted in NF-1. This is a very variable condition and you could be so mildly affected you don't even know you have it.

Phenylketonuria, or PKU, is characterized by an inability to metabolize an amino acid called phenylalanine. Buildup of the chemical causes mental retardation, but state-mandated screening programs are able to identify newborns with PKU so that a special phenylalanine-free diet can be started to prevent retardation and other problems. If you were diagnosed with PKU as a child, a special diet is called for during pregnancy. You should consider carrier screening if you have a family history of the disease.

Sickle cell disease is a blood disorder caused by a mutation in the gene that expresses the hemoglobin protein. The disease is characterized by anemia and periodic episodes of pain. Hemoglobin, the substances that carries oxygen in red blood cells, forms uncharacteristic, rodlike clusters in the cells, giving them a sickle shape and impeding their passage in small blood vessels. The cells create a bottleneck that deprives tissues of oxygen and causes pain. The cells die more quickly than normal red blood cells, leaving the body chronically short of such cells and anemic. About one in 12 African Americans is a carrier.

Thalassemia is a term that covers a range of related anemias that vary in severity. A baby with thalassemia major may appear normal during the first year but subsequently develops symptoms such as jaundice (yellowed skin) and low appetite. If untreated, enlargement of the liver and spleen can occur, sometimes leading to heart failure or heightened susceptibility to life-threatening infections.

Von Hippel-Lindau disease (VHL) is a rare, genetic multi-system disorder characterized by the abnormal growth of tumors in certain parts of the body (angiomatosis). The tumors of the central nervous system (CNS) are benign and are comprised of a nest of blood vessels and are called hemangioblastomas (or angiomas in the eye). Hemangioblastomas may develop in the brain, the retina of the eyes, and other areas of the nervous system. Other types of tumors develop in the adrenal glands, the kidneys or the pancreas. Gene testing is available.

Recessive Genetic Conditions More Prevalent in Individuals of Ashkenazi Jewish Descent

Canavan disease is a neurodegenerative disease characterized by lack of the aspartoacylase enzyme, which is critical for central nervous system development and function. The progression is similar to Tay-Sachs disease, and affected children usually die by age five. Your doctor, even an ob/gyn, may not be aware of the risk for Canavan disease. The carrier rate is about one in 40 among Ashkenazi Jews.

Congenital deafness can be caused by one of two changes in a gene called Connexin 26. About one in 21 individuals of Ashkenazi Jewish descent has one of the two mutations.

Cystic fibrosis (see general list)

Gaucher disease Type I is a disorder caused by a lack of glucocerebrosidase, an enzyme that helps clear glucocerebroside from cellular structures called lysosomes. The condition can lead to slower growth in children, bone degeneration, anemia, enlargement of the spleen and liver, and thrombocytopenia. A replacement enzyme treatment is available, but the product is expensive-in excess of $100,000 per patient annually. The carrier rate among the Ashkenazi is between one in 10 and one in 15. Not everyone who inherits two Gaucher disease mutations develops the disease or is aware of it.

Tay-Sachs disease is characterized by absence of hexosaminidase A, an enzyme that breaks down GM2-ganglioside. Without this enzyme, fat builds up in the central nervous system, leading to neurological degeneration. Afflicted children become symptomatic at around six months, and the disease is usually fatal in children within a few years. (Adult-onset forms of Tay-Sachs disease are rarer and less severe.) Carrier screening can be done on a blood sample looking at DNA mutations or enzyme levels, since carriers have reduced levels. A combination of enzyme level and mutation studies is the most accurate test. The carrier rate among the Ashkenazi Jewish population is about one in 25; the rate is about one in 50 among French Canadians, Cajuns and Irish.

Other conditions with a higher carrier rate in the Ashkenazi Jewish population for which testing is available include:

* Bloom syndrome, a chromosome breakage disorder. Symptoms include growth retardation, skin discoloration and typical facial features. The disease often leads to cancer and sometimes mental retardation. The carrier rate among Ashkenazis is about one in 100.

* Familial Dysautonomia is a disease that causes the autonomic and sensory nervous system to malfunction. Symptoms include the absence of tears, taste buds, and deep-tendon reflexes. The gene was recently identified and carrier screening is available to the general population. That carrier rate is one in 30.

* Fanconi anemia, a DNA repair disorder that leads to a range of symptoms including thumb and arm abnormalities, skeletal abnormalities, kidney problems, skin discoloration, small head or eyes, mental retardation or learning disabilities, gastrointestinal difficulties, small reproductive organs in males and defects in tissues separating heart chambers. There are at least five genes implicated Fanconi anemia-and it only takes one of them going awry to cause the disease. Type C accounts for most cases of FA in the Ashkenazi Jewish population. Commercial testing is available for this mutation. The carrier rate among the Ashkenazi Jewish population is about one in 89.

* Niemann-Pick disease is a metabolic disorder caused by insufficient quantities of sphingomyelinase. The result is accumulation of the fatty substance sphingomyelin in the spleen, liver, lungs, bone marrow and, in some patients, the brain. Patients with Type A-predominantly individuals of Ashkenazi Jewish descent-rarely live beyond 18 months. Commercial carrier testing is available for Type A. The carrier rate among the Ashkenazi population is about one in 90.

* Mucolipidosis Type IV is a rare autosomal recessive disease with a carrier rate of 1 in 140 among Ashkenazi Jews. It is a progressive neurological disorder with symptoms beginning in the first year of life. Survival is rare, and the child has severe developmental delays. There is no treatment available.

Other Diseases in Ashkenazi Jews

* Torsion dystonia is a muscle-control disorder with an autosomal dominant inheritance pattern, but only a 30 percent penetrance, which means it takes only one defective gene to create the possibility of the disease, but only 30 percent of individuals who inherit the mutation will develop the disease. A genetic test can determine whether a person of Ashkenazi Jewish descent has the mutation that produces 90 percent of the cases in that population. Though the frequency of the gene is still uncertain, it occurs in no more than one in 2,000 Ashkenazi Jewish individuals.

FDA Approves Lower Dose of Prempro, A Combination Estrogen and Progestin Drug for Postmenopausal Women. Press Release, March 13, 2003.

"FDA Approves New Labels for Estrogen and Estrogen with Progestin Therapies for Postmenopausal Women Following Review of Women's Health Initiative Data." FDA News/Press Release. January 8, 2003. Accessed Dec. 2003.

Lacey, James V., et al. "Menopausal Hormone Replacement Therapy and Risk of Ovarian Cancer." JAMA 2002. Vol. 288:334-341.368-369.

Grady D, Herrington D, Bittner V, et al, for the HERS Research Group. Heart and estrogen/progestin replacement study follow-up (HERS II): Part 1. Cardiovascular outcomes during 6.8 years of hormone therapy. JAMA 2002;288:49-57.

Hulley S, Furberg C, Barrett-Connor E, et al, for the HERS Research Group. Heart and estrogen/progestin replacement study follow-up (HERS II): Part 2. Non-cardiovascular outcomes during 6.8 years of hormone therapy. JAMA 2002;288:58-66.

Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321-333.

"Women's Health Initiative," National Heart, Lung and Blood Institute. Updated Oct. 2003; accessed Dec. 2003.

The Menopause Guidebook: Helping Women Make Informed Healthcare Decisions through Perimenopause and Beyond. North American Menopause Society: May 2003; Accessed Dec. 2003.

About genetics services (overview material). GeneTests (Collaborative effort of the NIH, HHS, University of Washington and Children's Hospital and Regional Medical Center of Seattle). Revised 2000. Accessed Jan. 2002.

Genzyme Genetics patient information: Conditions and Tests. Accessed Dec. 2003.

Ashkenazi Jewish Genetic Diseases. Albert Einstein Health Care Network. Updated Sept. 2001. Accessed Dec. 2003.

Burke, Wylie, E Thomas, et al. Hereditary hemochromatosis: gene discovery and its implications for population-based screening. Journal of the American Medical Association. July 8, 2000; Vol. 280, pp. 172-78.

Celiac Disease. National Institute of Diabetes and Digestive and Kidney Disease. July 2003. Accessed Dec. 2003.

Facts About Cystic Fibrosis. National Heart, Lung and Blood Institute. Accessed Jan. 2002.

Facts about Fragile X Syndrome. National Institute of Child Health and Human Development. Last modified Nov. 2002. Accessed Dec. 2003.

Facts About Sickle Cell Anemia. National Heart, Lung and Blood Institute. Accessed Jan. 2002.

Multiple Endocrine Neoplasia Type 1. National Institute of Diabetes and Digestive and Kidney Diseases. Last reviewed June 2002. Accessed Dec. 2003.

Hemochromatosis. National Institute of Diabetes and Digestive and Kidney Disease. Aug. 2002. Accessed Dec. 2003.

Huntington's Disease. National Institute of Neurological Disorders and Stroke. Last reviewed July 2001. Accessed Jan. 2002.

Neurofibromatosis. National Institute of Neurological Disorders and Stroke. Reviewed May 2003. Accessed Dec. 2003.

NHGRI Glossary of Genetic Terms. National Human Genome Research Institute. Accessed Dec. 2003.

NINDS von Hippel Lindau Disease Information Page. National Institute of Neurological Disorders and Stroke. Reviewed May 2002. Accessed Dec. 2003.

Understanding Alpha-1 Antitrypsin Deficiency. National Heart, Lung and Blood Institute. Accessed Jan. 2002.

MEDLINEplus: Alpha-1 Antitrypsin Deficiency. Updated Jan. 2002. Accessed Jan. 2002.

Understanding Gene Testing. National Cancer Institute. Accessed Jan. 2002.

Editorial Staff of the National Women's Health Resource Center 2002/12/20 2005/05/12 Today, there are hundreds of different genetic tests, some of them for relatively common disorders such as cystic fibrosis, and some for very rare diseases. A genetic test is fundamentally different from other kinds of diagnostic tests you might take. BRCA,Chorionic villus sampling,Chromosome,Genetic counseling,Genetic testing,Genetics,Maternal serum screening,Preimplantation genetic diagnosis
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Date:May 12, 2005
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