Although genetic testing includes the analysis of DNA, RNA, chromosomes, proteins, and certain metabolites, it is DNA- and RNA-based molecular genetic testing that has catapulted into mainstream medicine during the past decade.^1,2 Molecular genetic testing is now available on a clinical basis for more than 750 inherited conditions.³ There are three types of these heritable disorders: (1) single-gene disorders caused by a mutation in one gene that is inherited in a Mendelian fashion (i.e., autosomal dominant, autosomal recessive, X-linked); (2) contiguous gene disorders caused by deletion or duplication of multiple adjacent genes that are inherited in a Mendelian fashion (e.g., 22q11.2 deletion, which is almost as common as Down syndrome); and (3) mitochondrial disorders caused by mutation or deletion of mitochondrial DNA that is inherited maternally (e.g., Kearns-Sayre syndrome). The prevalence of the most common of these heritable disorders is one per 1,000 persons, but most are considerably rarer. The common complex disorders that comprise the “bread and butter” of primary care, such as breast cancer, hypertension, asthma, and cleft lip, are attributed to the interaction of subtle variations in multiple genes and environmental factors, and they are not yet amenable to molecular genetic testing. Thus, existing molecular genetic tests are not useful as population-based screening tests to stratify patient risks for the purpose of introducing risk-reducing medications or lifestyle changes.

Molecular genetic testing for heritable disorders is used for the following purposes: (1) diagnosis, in which testing confirms or excludes a known or suspected genetic disorder in a symptomatic patient; (2) confirmation of a diagnosis, in which testing establishes a diagnosis suspected in a patient who does not meet diagnostic criteria; (3) predictive testing, which is offered to asymptomatic persons who, based on their family history, are at risk for developing a disorder; (4) carrier testing, which identifies persons with a genetic mutation for a disorder inherited in an autosomal recessive or X-linked recessive manner; and (5) prenatal diagnosis, in which testing determines whether a fetus is affected with a particular disorder.

In predictive testing, carrier testing, and prenatal diagnosis, it is essential that one affected family member be tested before testing at-risk relatives. Testing of an affected relative is required for one of two reasons. First, it can confirm the diagnosis. For example, the molecular genetic testing for Huntington’s disease (HD) involves assessing the size of the CAG trinucleotide repeat in the HD gene, a test that can be performed and interpreted accurately for any symptomatic person. However, mutations in other genes, such as HDL2, can mimic HD. Thus, if an affected person with an unconfirmed clinical diagnosis of HD actually has a mutation in HDL2, testing at-risk asymptomatic relatives for mutations in the HD gene will yield falsely reassuring normal results. Conversely, testing for mutations in HDL2 will yield the accurate information (i.e., the disorder for which relatives are at increased risk). Second, testing the affected family member is important to detect the family-specific mutation. For example, more than 825 mutations causing familial adenomatous polyposis have been identified in the APC gene. Each mutation “runs true” in a family (i.e., blood relatives are at increased risk only for the mutation known to be in the family). Before predictive testing can be offered to an at-risk family member, the cancer-causing mutation specific to that family must be identified to assure accurate interpretation of “negative” test results.

Genetic testing differs from traditional medical testing in two ways. First, genetic test results always have implications for disease risk for the patient’s family as well as the patient. Second, genetic testing may be used for the sole purpose of personal decision making rather than medical care. For example, two people who are carriers for cystic fibrosis might choose to have prenatal diagnosis and terminate an affected fetus, have preimplantation genetic diagnosis, adopt, or decide not to have children. Asymptomatic at-risk persons whose predictive testing identifies a 100 percent risk for HD may elect to shorten their formal education or choose different investment options.

Genetic counseling is as essential to care of the patient with a genetic disorder as the testing itself. Genetic counseling involves determining the advantages and disadvantages of testing and the potential implications of the test results for both the patient and the patient’s family; education about the nature and cause of the inherited disorder; information to promote informed medical and personal decision making; and psychosocial support and referral. Although genetic counseling can be provided by any health care provider with the appropriate experience and training, family physicians may choose to refer patients to a genetics professional because of the time needed to become familiar with the relevant aspects of the disorder, testing, management, and disease-specific psychosocial support services. Other factors include the time needed to identify at-risk relatives and to meet with the patient and interested family members to discuss the issues most important to them and poor reimbursement by third-party payers.⁴

Genetics professionals can be identified individually through the Web sites of their professional organizations. Genetics clinics can be located by city and state, services (e.g., adult genetics, cancer genetic counseling and risk assessment, pediatric genetics, preimplantation genetics, prenatal genetics, telemedicine), and specialty through the GeneTests Clinic Directory (http://www.genetests.org).³