Overview

Key Points

We stand at a remarkable time in history regarding our understanding of how variations in the human genome contribute to health and disease. At least some of this progress can be attributed to the technologies developed to complete the Human Genome Project. The tools of genomics and molecular biology have begun to unlock the fundamental underpinnings of previously enigmatic conditions, shedding light on the fundamental nature of the human species.

The most exciting developments since 2005 are related to the genetics of common disease, a mainstay of primary care medicine. For the first time, geneticists have been able to use a very powerful technique known as genome-wide association study (GWAS) to identify human genome variations associated with common disease risk. Hundreds of risk markers known as single nucleotide polymorphisms (SNPs) have been reliably associated with the presence of a long list of common conditions. Although each individual marker confers only a small risk of disease (which greatly limits their use in the clinic to predict risk in individual patients), each has helped to better define disease pathogenesis (Kraft and Hunter, 2009; Manolio et al., 2008). With the advent of low-cost whole-genome sequencing, discoveries related to disease risk, prognosis, and treatment relevant to primary care should accelerate (Feero et al., 2010). Most chapters in a family medicine textbook will eventually include the relevant information to the specific topic derived from genetics and genomics.

We are at an early stage in the discovery process, and our embryonic understanding of the human genome is not easily yielding improvements in clinical care. This perspective is often lost in the media hype and attention given to the latest genetic discovery. The lack of a rapid translation from a new discovery to a proven clinical application (e.g., genetic test, targeted therapy) frustrates clinicians and patients alike and can lead to unrealistic and potentially harmful expectations. Clinicians should recognize where the application of knowledge from genetic discovery is of proven benefit, and where it is not. Perhaps most importantly, physicians should recognize that a substantial and rapidly expanding number of genomic applications fall into a gray area of unexplored benefit. It is incumbent on providers to seek additional information from a reputable source when in doubt.

Genetics and Evidence-Based Medicine

As a discipline, clinical genetics developed in an environment that focused on the diagnosis and treatment of rare, or at least uncommon, disease. Often, large numbers of patients were not available for clinical trials, and in many cases the severity of the conditions made randomized placebo-controlled trials (RCTs) untenable. This contrasts with evidence-based medicine (EBM), which primarily deals with common conditions and values large, prospective RCTs, as well as the societal consequences of individual medical choices. As genomic discoveries increasingly impact health care for common conditions, new applications should be evaluated through a lens of evidence of benefit. Established groups that follow EBM precepts, such as the U.S. Preventive Services Task Force (USPSTF, 2009), have addressed screening and testing for hereditary breast and ovarian cancer syndrome and hemochromatosis. The U.S. Centers for Disease Control and Prevention (CDC) has established newer groups such as the Evaluation of Genetic Applications in Practice and Prevention (EGAPP, 2009) specifically to review the evidence supporting genetic and genomic applications intended for health care use. Modeled after USPSTF, EGAPP has begun to produce evidence reviews and recommendations (Table 44-1). Considerable growing pains will occur as EBM and genomic medicine intersect.

Table 44-1 Select Evidence-Based Recommendations for Genetic/Genomic Applications

Family History: Best Guide to Genetic Components of Disease

Key Points

Family history is arguably the single best tool for recognizing genetic components of disease in the primary care setting. In the context of single-gene disorders, family history has proved valuable for generations of clinicians and plays a major role in making a diagnosis and identifying at-risk individuals. Family physicians should be familiar with common patterns of inheritance of single-gene disorders, including X-linked recessive, X-linked dominant, autosomal dominant, autosomal recessive, and multifactorial/complex (Table 44-2). Classically, the three-generation genetic history known as a pedigree or genogram has been taught as the “gold standard” of family history collection. Certainly, once a potential genetic issue has been identified, a family physician should be comfortable in collecting and accurately representing a complete family history. However, taking a complete family history can be time-consuming, and on a practical level, it is not always possible to collect in the context of a brief office visit. It is perfectly reasonable to gather, review, and update family history longitudinally.

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

Common diseases such as type 2 diabetes, coronary artery disease, and cancer also cluster in families. Family history captures both hereditary and environmental risks and is an important component of many validated risk algorithms for these and other conditions. Recent attention has focused on the systematic collection of family history as a screening tool in primary care settings. Family history information supplied by patients is generally fairly accurate for a wide range of conditions. However, few well-designed trials have examined health outcomes associated with use of family history as a screening tool (NIH Consensus Development Program, 2009).

Given competing demands on family physicians’ time and resources, what genetic family history is the most important to capture? A national collaboration of primary care and genetics professionals has developed mnemonics to help clinicians think genetically as they provide patient care (Burke et al., 2001). FamilyGENES highlights “red flags” that signal a genetic concern, as follows (Whelan et al., 2004):

SCREEN (for familial disease) uses the following set of family history questions to uncover genetic implications:

Electronic health record (EHR) systems seldom offer efficient and complete ways to collect and represent family history information. National efforts are underway to address this deficiency. Patient-completed paper and electronic tools provide another way to obtain a detailed genetic history. The U.S. Surgeon General’s Family History Initiative (2005) includes a web-based tool that can be completed by patients, stored on their local computer, and shared with relatives and their health care providers in pedigree or table format (My Family Health Portrait; https://familyhistory.hhs.gov/). This free, easy-to-use tool is an excellent way for patients with Internet access to record family history and is time-saving for the clinician. The family history collected by the tool is now stored using emerging data standards that allow the data to be shared with EHR and personal health record systems. Alternatively, a number of organizations have created paper family history tools for patients and providers that are available on the Internet.

Genetic Testing

Key Points

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.

Table 44-3 Types of Genetic/Genomic 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.

Examples of Genetic Testing

Preconception and Prenatal Screening

Genetic screening or testing can occur either before conception or during the pregnancy. When possible, screening or testing before a pregnancy is ideal, because this provides the broadest range of choices if increased risk of a genetic defect is detected. Preimplantation genetic testing is available for an increasing number of conditions but is costly and not accessible to many individuals. Most genetic evaluations occur after the pregnancy is established. The ability to detect genetic defects has grown rapidly over the past decade. Many ethical issues exist in both the preconception and the prenatal screening or testing environment, including the course of action if the fetus is found to have an incurable, life-altering condition. Common indications for prenatal testing are advanced maternal age, previous child with a chromosomal abnormality, family history of abnormality or single-gene disorder, family history of neural tube defect or other structural abnormality, abnormalities identified in pregnancy (e.g., on ultrasound), parental consanguinity, recurrent miscarriages, previous unexplained stillbirth, parental ancestral origin, and use of certain medications. The American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Geneticists (ACMG) have developed guidelines for recommended tests (Solomon and Feero, 2008). However, these guidelines are often based on consensus or expert opinion and do not always agree.

High-resolution ultrasound and quadruple serum panel are screening tests for congenital anomalies associated with a variety of genetic conditions. More invasive testing, such as chorionic villus sampling (CVS) and amniocentesis, may provide more accurate diagnosis, but at the cost of higher risk of complications. Recent guidelines suggest that amniocentesis be offered to all pregnant women to aid in the detection of Down syndrome (ACOG, 2007). The family physician should evaluate the risks and benefits of all forms of prenatal genetic screening or testing, discuss them with the patient and her partner, and make referrals to health care providers with genetics expertise as appropriate.

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