Key Points

• Knowledge of the indications for and limitations of genetic testing is relevant to common clinical situations in family medicine.

• The context of testing and its limitations are important for proper interpretation.

• Pretest and post-test counseling are currently recommended for genetic testing, although the need for such counseling in all testing situations is controversial.

Table 44-2 Patterns of Inheritance Often Encountered in Primary Care

Pattern of Inheritance

Characteristics Of Family History

Example Conditions

X-linked recessive

Males affected more than females, maternal inheritance, 50% risk of female carrier sons affected

X-linked color blindness X-linked muscular dystrophy

X-linked dominant

Males and females may be affected, males more severe, daughters of affected males affected, male and female transmission

Fragile-X syndrome

Autosomal dominant

Affected individuals usually in every generation, 50% probability of affected individuals having affected offspring, M = F

Huntington's disease Hyperkalemic periodic paralysis Lynch syndrome Marfan's syndrome

Autosomal recessive

Often multiple affected individuals in same generation, skipped generations, 25% risk of affected child for carriers, M = F

arAntitrypsin deficiency

Cystic fibrosis

Sickle cell disease

Most inborn errors of metabolism

Multifactorial

Clustering of cases in families, risk to first-degree relatives high; consequences of shared environment might be evident.

Coronary artery disease Types 1 and 2 diabetes Many cancers

• Genetic testing results can have implications for the family, and providers generally have a duty to warn potentially affected members.

• Family physicians should be involved in ordering, interpreting, and managing the consequences of genetic testing with health implications.

Identifying what constitutes a genetic or genomic test can be challenging. Traditionally, a genetic test measures changes in the sequence of deoxyribonucleic acid (DNA), but a "genetic test" can also be a measure of a protein or metabolite (Table 44-3). From this perspective, a fasting lipid panel could be considered a genetic test. Also, a genetic test does not always need to be relevant to other family members, as when an individual's cancer cells are tested for mutations that affect prognosis and therapy. In some cases a family physician's most important role is simply to reassure low-risk individuals that they do not need genetic testing.

The indications for genetic testing include confirming a diagnosis, identifying disease risk, and guiding therapeutic interventions. A genetic test can be done using many types of specimens, although testing for mutations in DNA is often done on DNA extracted from whole blood, saliva, or a cheek swab. Some tests look for only specific mutations, whereas others scan for all mutations in a specific DNA region. Testing costs can range from $100 to thousands of dollars, depending on the complexity and patent status of the test. Often, testing an affected family member first is the preferred strategy. Without knowing the mutation present in a family, an asymptomatic patient's negative test result may not be informative, because the particular test done may not include the mutation affecting that family.

Family physicians should be aware that genetic testing may have implications for the extended family as well as the patient. For example, studies with Huntington's patients have shown that genetic test results, whether positive or negative, have significant implications for patients and their families. This includes depression, lifestyle behavior changes, and relationship changes among family members. Those testing negative may have survivor's guilt or may be treated as being outside the family. Patients can benefit from counseling about implications before undergoing genetic testing that is both highly predictive and associated with profound health consequences (Martin and Wilikofsky, 2004). For genetic tests that are less predictive or are associated with conditions with less profound health consequences, the benefits of formal genetic counseling are less clear-cut.

Obtaining and interpreting molecular tests for DNA mutations often has unique considerations. First, it is important to order the correct test for the patient's condition; this is not always obvious, particularly when multiple tests are available. Second, the presence of a mutation in an asymptomatic individual only rarely predicts disease onset, course, or severity. This is particularly true for the multitude of recently discovered SNP markers associated with risk for common complex conditions. Third, absence of a known causal mutation in a gene may not mean that an individual is at no or low risk of disease. For example, in families meeting the clinical criteria for hereditary breast and ovarian cancer syndrome, testing for mutations in the BRCA1 or BRCA2 occasionally fails to detect a mutation in affected members. The absence of detectable mutations in affected individuals means that the test is essentially uninformative, and the risk to asymptomatic family members needs to be estimated from the clinical scenario and is not that of the average population (GeneTests, 2009). Because of the complex factors involved, genetic tests are frequently ordered by physicians with particular expertise regarding the condition for which testing is being considered. Currently, there are insufficient genetics professionals in all U.S. areas to handle the counseling associated with genetic tests. As a result, primary care physicians will most likely be providing more genetic counseling and testing in the future. The next section provides a more in-depth look at settings in which different types of genetic testing are relevant to primary care.

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