Genetic health consultation
3. Infancy and Childhood
4. Adolescence and Adulthood
5. What are the limitations of gene testing?
6. What are the risks of gene testing?
7. Genetics FAQ
When people hear the word "genetics" they often think of pregnant women, children with birth defects, and childbearing couples. This term rarely conjures up thoughts of healthy adolescents or adults. Therefore, you may not readily recognize everyone who might benefit from a genetic consultation.
While there are no established criteria for the types of patients that merit genetic consultation, there are some general rules you can use. The following is a list of reasons for referral. This list has been divided into the different stages in the life cycle.
Prior to conception there are a number of factors that might lead you to conclude a woman/couple could benefit from a consultation. The reasons for referral include the following:
* A positive family history of a genetic disorder (e.g., fragile X syndrome, muscular dystrophy, cystic fibrosis) and concern about recurrence
* Members of a high-risk ethnic group
* Previous infertility or sterility problem
* Exposure to potential teratogenic or mutagenic agents
* Maternal health (e.g., diabetes, PKU, epilepsy)
* Consanguineous marriage
* Anxieties over childbearing
* Two or more prior miscarriages or pregnancy losses
* A previous stillborn child
* A previous child with a genetic or chromosomal disorder or birth defect (e.g., neural tube defect, Down syndrome, PKU)
The goal of preconception counseling is to provide couples with the information necessary to make informed decisions about reproduction and the available testing, intervention or treatment options. Members of high-risk ethnic groups, for instance, should be told that carrier testing is available. Individuals who carry a balanced chromosome rearrangement should be offered the option of prenatal diagnosis in future pregnancies, and women who are using teratogenic agents should be counseled about the associated risks.
The advantage of preconception counseling is that it is possible to pursue genetic studies prior to pregnancy. In the absence of time constraints, a tiered evaluation can be done. Medical records can be requested and reviewed, laboratory tests can be ordered and analyzed systematically, and extended family studies can be undertaken as needed.
Other reasons to pursue genetic studies prior to conception include the fact that some test results are unreliable during pregnancy (e.g., hexosaminidase enzyme levels in pregnant women who carry the gene for Tay-Sachs disease). Certain prevention strategies may only be effective if instigated prior to conception. For instance, all women of childbearing age should take 0.4 mg of folic acid daily to decrease the risk of having a child with a neural tube defect. Women who have had an affected child should take 4 mg of folic acid daily for three months prior to conception. This has been shown to significantly decrease the recurrence of NTDs in subsequent pregnancies.
Women with health problems are more likely to have babies with birth defects. For example, babies born to insulin dependent diabetic women are more likely to have congenital heart defects, genitourinary defects, and caudal regression sequence, unless the diabetes is strictly controlled prior to conception and during the first trimester. Mothers with PKU need to have normalized levels of phenylalanine prior to conception to prevent mental retardation in the child. Women on anticonvulsant medication should be switched to the least teratogenic drug, and the smallest clinically effective dose.
back to top
During pregnancy, there are tests that can be done to determine whether or not the fetus has a chromosome abnormality, certain single gene disorders or structural abnormalities. Women who might benefit from prenatal diagnostic tests and counseling include the following:
* Women who will be 35 years old or older at delivery
* A woman and/or her partner who are known to carry genes coding for a genetic disorder
* A woman or her partner who are known to carry a chromosome rearrangement or abnormality
* Couples with a family history of a neural tube defect
* Couples with a previous child born with multiple congenital anomalies or a chromosome abnormality
* Women with an abnormal level of maternal serum alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), or estriol (uE3)
* Women exposed to an infectious disease, radiation, drugs or other environmental agents during pregnancy
Due to the increased risk of chromosome abnormalities in babies born to women over the age of 34, the American College of Obstetricians and Gynecologists recommends that all pregnant women who will be 35 years or older at delivery should be offered the option of prenatal diagnosis. The College also recommends that a maternal serum marker screen be offered to all pregnant women between 15 and 18 weeks gestation.
Many single gene disorders can be diagnosed prenatally. As the technology is changing rapidly, if the patient or her partner has a single gene disorder or if they have a child with a recessive genetic condition, it is important to determine if new prenatal tests have been developed since the last pregnancy.
Women who are exposed to teratogenic agents during pregnancy may also benefit from genetic counseling. In some instances the risk of an abnormality may be much lower than first assumed and counseling may reduce maternal anxiety. In some cases, further diagnostic studies may be proposed to assess fetal development or to rule out the presence of obvious structural defects associated with exposure to a specific agent. Only rarely are the risks of a birth defect high enough to make pregnancy termination a reasonable option.
back to top
Factors that might lead you to conclude that an infant or child might benefit from a genetic evaluation include the following:
* A history of intrauterine growth retardation or failure to thrive
* Abnormal growth patterns (short stature, obesity, excessive growth)
* Ambiguous or abnormal genitalia, early onset of puberty
* Microcephaly, macrocephaly or craniosynostosis
* Psychomotor delay or mental retardation
* Hypotonia, hypertonia
* A parent, sib or other relative who has problems similar to those observed in the patient
* Abnormal or unusual facial features
* Abnormal body and limb proportions, asymmetry
* Major or minor congenital anomalies
* Metabolic disorder
* Muscular weakness
* Bleeding tendency
* Blindness or deafness
* A significant regression in developmental progress
* An unusual body odor
* Excessive unexplained vomiting
* Unusual behaviors, especially when associated with minor malformations (hand biting, hand flapping, autistic symptoms, abnormal sleep patterns, etc.)
Major malformations are often noted at delivery or shortly after birth, and a genetic consultation is usually requested prior to discharge from the hospital. In some cases, establishing a diagnosis in the newborn period may be critical if informed decisions are to be made about surgery or the degree of medical intervention provided to sick babies. In infants with ambiguous genitalia, for example, it is important to establish the chromosomal sex and rule out the diagnosis of congenital adrenal hyperplasia (CAH); as infants with CAH may experience a life threatening deficiency of cortisone under stress.
While major malformations are often diagnosed prior to discharge, some problems emerge over time. Changes in the normal patterns of growth and development may be the first clue that a child has an underlying genetic disorder. Changes in a child's health and capabilities is another reason for referral. Some inborn errors of metabolism, for example, are accompanied by acute encephalopathy, lethargy, hypertonia or hypotonia, and seizures caused by the toxic effects of metabolites on the brain. Other inborn errors of metabolism may cause progressive encephalopathy later in infancy or childhood with gradual spasticity or ataxia, dementia, visual or hearing loss, and enlargement or abnormal function of organs such as the liver, heart, kidneys, and joints.
back to top
Some reasons for adolescent and adult referrals for a genetic evaluation and counseling are listed below:
* Abnormal sexual maturation
* Amenorrhea (failure to menstruate), delayed puberty
* Growth retardation
* Excessive tall stature
* A diagnosis of an adult onset genetic disease (e.g., Huntington disease, Marfan syndrome, myotonic dystrophy
* A positive history of familial disorders (e.g., colon cancer, breast/ovarian cancer, familial hypercholesterolemia, psychiatric or behavioral disorders)
* Members of high-risk groups who want to pursue carrier testing for single gene disorders or chromosome abnormalities (e.g., Tay-Sachs disease, Duchenne muscular dystrophy, hemophilia, sickle cell anemia, translocation carrier)
* Paternity testing
* Questions about genetic diseases or birth defects in immediate or extended family members
Changes in the normal patterns of sexual development or growth during the teen years should prompt a genetics referral. The option of carrier testing should be offered to individuals belonging to high-risk groups. Individuals diagnosed with an adult onset genetic condition should be referred to discuss the genetics of their condition and the risk to other family members. Risk assessment programs are available in most areas for people with a family history of certain types of cancer and other genetic conditions.
back to top
First, current gene tests cannot provide a satisfactory answer for everyone who seems to be at risk for inherited breast or colon cancer. In some families, multiple cases may reflect shared environmental exposures rather than inherited susceptibility. Even when an inherited gene is to blame, it is not necessarily the test gene; the BRCA1 gene mutation, for example, is found in only about half of the families with hereditary breast cancer.
Second, despite major advances in DNA technology, identifying mutations remains a great challenge. Many of the genes of greatest interest to researchers are enormous, containing many thousands of bases. Mutations can occur anywhere, and searching through long stretches of DNA is difficult.
In addition, a single gene can have numerous mutations, not all of them equally influential. The cystic fibrosis gene, for instance, can display any one of more than 300 different mutations, which cause varying degrees of disease; some seem to cause no symptoms at all. Thus, a positive test does not guarantee that disease is imminent, while a negative test - since it evaluates only the more common mutations - cannot completely rule it out.
Furthermore, predictive tests deal in probabilities, not certainties. One person with a given gene, even one that is dominant like the hereditary breast cancer gene, may develop disease, while another person remains healthy, and no one yet knows why. A gene may respond to the commands of other genes or be switched on by an environmental factor such as sunlight.
Perhaps the most important limitation of gene testing is that test information often is not matched by state-of-the-art diagnostics and therapies. Many diseases and many types of cancer still lack optimal screening procedures; it is often not possible to detect an early cancer even in an individual with a known predisposition.
In inherited breast cancer, frequent screening with mammography offers the best chance of early detection, but falls short of prevention. Moreover, mammography is least effective in the glandular breasts of young women, the very ones at greatest risk from an inherited susceptibility. For the moment, the best assurance of prevention may lie in drastic and costly surgery to remove the breasts - but even a total mastectomy can leave some breast cells behind. As for the ovarian cancer that threatens high-risk families, available screening measures often cannot discover disease in time. Here, too, women in high-risk families often opt for prophylactic surgery to remove the ovaries. To date, however, neither type of prophylactic surgery has been proven to prevent completely the occurrence of cancer.
Scientists are actively studying interventions aimed at the prevention of cancer. For example, ongoing clinical trials are evaluating the use of tamoxifen, an anticancer drug, as a breast cancer preventive. However, such approaches are still in the realm of research.
The physical risks of the gene test itself - usually no more than giving a blood sample - are minimal. Any potential risks have more to do with the way the results of the test might change a person's life.
Psychological impact. First, there are the emotions aroused by learning that one is - or is not - likely to develop a serious disease. Many people in disease families have already seen close relatives fall victim to the disorder. The news that they do indeed carry the disease gene can elicit depression, even despair.
Few studies to date have looked directly at the outcome of gene testing for cancer. One study found that, after 3 to 6 weeks, the women identified as gene carriers experienced persistent worries, depression, confusion, and sleep disturbance. Even half of the noncarriers reported that they continued to worry about their risk status.
A gene test confirming the risk of a serious disease
can trigger profound psychological consequences.
Family relations. Unlike other medical tests, gene tests reveal information not only about ourselves but about our relatives, and the decision to have a gene test, as well as the test results, can reverberate throughout the family. If a baby tests positive for sickle-cell trait, for example, it follows that one of his or her parents is a carrier. It is also possible for gene tests to inadvertently disclose family secrets involving paternity or adoption.
Emotions elicited by test results can produce a shift in family dynamics. Someone identified as carrying the gene may feel anger, while one who has escaped may be overwhelmed by guilt for avoiding a disease that afflicts a close relative.
Family issues are especially prominent in research programs where genetic linkage tests depend on testing many members of the same family. Some family members may not want to participate in the study or know their genetic risks. People considering gene tests may want to find out how their relatives would feel about knowing whether or not they have a disease gene or allowing the information to be given to others.
Someone who elects to have a gene test needs to consider whether or not to share the test results with other members of the family. Do they want to know? Who should be told - spouse, children, parents, fianc? Should someone in a high-risk family be tested before she or he marries? What will a positive test mean to one's relationships? If one chooses not to learn the results of the family's gene testing, can such a request be respected? How?
The question and issues raised by gene testing
can challenge family and other personal relationships.
Medical choices. Someone who tests positive for a cancer susceptibility gene may opt for preventive or therapeutic measures that have serious long-term implications and are potentially dangerous or of unproven value. In the first family to be tested for a BRCA1 mutation, for instance, some women chose surgery to remove their breasts - and ovaries, too, after childbearing was completed. Other families told the genetic counselor that they were not interested in even discussing surgery.
Finding ways to ensure the confidentiality of gene test
results is a major concern.
Privacy. Our genes hold an encyclopedia of information about us and, indirectly, about our relatives. Who should be privy to that information? Will a predisposition for cancer, for instance, remain secret - or could the information slip out? The concern is that test results might someday be used against a person. Some people have been denied health insurance, some have lost jobs or promotions, and some have been turned down for adoptions because of their gene status.
Small research studies have conscientiously established safeguards to keep DNA results under wraps. Assurances of confidentiality may be more difficult to come by when larger numbers of people have access to the results. Clinical test results are normally included in a person's medical records. Even if gene testing information could be kept out of the medical record, a person's need for more frequent medical checkups, for example, could provide a tip-off to susceptibility. Might a genetic flaw constitute a "preexisting condition" that would be excluded from insurance coverage?