A common misconception in the medical community is that genetic disorders consist of a collection of extremely rare conditions not often relevant to day-to-day clinical practice. In fact, essentially every medical condition affecting mankind has at least some genetic component to its etiology. The study of how mutations in single genes cause rare disease (genetics) is gradually being eclipsed by research on how mutations in multiple genes interact with each other and the environment to result in health and disease (genomics). Knowledge derived from genomic discoveries is reshaping the underpinnings of much of medical practice, and will continue to do so for decades to come. At a practical level, recent advances have taught us a tremendous amount about the basis of common conditions like diabetes, heart disease, and cancer. This new knowledge is being rapidly translated into approaches for disease risk assessment, prevention, and treatment. Likewise, the study of how genes affect drug metabolism (pharmacogenetics) is being increasingly used to inform drug prescribing (see Chapter 48). Importantly, primary care physicians should not lose sight of the fact that so-called rare single-gene disorders collectively comprise a significant proportion of pediatric and adult illnesses.

Primary care physicians are in a unique position to diagnose genetic disorders because they are often the first contact for patients and also provide care for multiple family members. Recognition of, and subsequent attention to, the presence of genetic risk factors for disease in an individual can be lifesaving for the individual and their relatives. Further, as pharmacogenetics becomes increasingly important to drug therapy, primary care providers will need to be aware of and comfortable with ordering and interpreting this type of testing prior to prescribing a variety of medications.

The recent advent of new “direct-to-consumer” (DTC) genetic tests purporting to inform consumers on genetic aspects of everything from their ear-wax type to their risk of developing serious medical conditions has garnered significant media attention and public interest. Many in the scientific community feel that tests such as “genome-wide scans” are being prematurely made available for clinical use outside of carefully controlled research environments. The DTC movement will place additional responsibility on primary care providers to become literate in genomics in order to responsibly guide patients seeking advice regarding such tests.

Collecting family history information and recognizing key symptoms and signs are the most important components in identifying genetically influenced disorders.

Family History

Most common diseases result from a combination of exposure to environmental factors and the effects of variations in multiple genes. Inherited variations confer individual risks that can be distinguishable from the population-based average, and hundreds of such variations have been discovered over the last several years for conditions ranging from schizophrenia to Parkinson to coronary artery disease. However, for most conditions the genetic variations discovered to date explain only a small fraction of the heritable component of disease risk in any given individual—for example in type 2 diabetes well over a dozen genetic variations have been discovered, yet collectively they explain only 5%-10% of heritable disease risk.

Obtaining a medical family history provides the most effective current method to rapidly determine if an individual is at genetic risk of developing common disorders. Additionally, for most individuals family history captures at least some of the environmental and cultural contributors to disease risk. For many common diseases patient reported family history of disease in first-degree relatives is highly sensitive and specific. Importantly, common disorders often have modifiable risk factors that can be addressed or for which screening interventions can be instituted (Table 47-1). Family history evaluation can also be useful in identifying rare conditions that may not otherwise be considered in a differential diagnosis. For example, a child with developmental delay may have other family members who have had developmental delays or more severe congenital abnormalities. The Office of the U.S. Surgeon General provides an excellent free patient-focused, web-based tool for family history collection called My Family Health Portrait.

Sometimes specific questions will suffice when screening for a particular disease. However, recording family medical history in the form of a pedigree (Figure 47-1) can provide a concise visual tool for recording and interpreting medical information. When obtaining or updating a pedigree, the following general information may be recorded: patient name; date recorded or updated; consanguinity (note relationship); ethnic background of each grandparent, if known; and name and credentials of the person who recorded the pedigree. It is often helpful to include a key that explains symbols used in the pedigree (see Figure 47-1). Specific information such as age, relevant health information, age at diagnosis, age at death (with year, if known), cause of death, infertility (if known), and information about pregnancies (including miscarriages, stillbirths, and pregnancy terminations, along with gestational ages of family members or their partners) is then obtained for each listed family member.

Open-ended questions, such as “describe any medical conditions that affect your mother,” provide the most information when obtaining a medical family history. It is often more efficient for patients to begin to generate their own family history at home, and several family history tools have been developed for use by patients. Family medical history may also be confirmed through medical record documentation.

Inheritance Patterns

A pedigree can help to identify a pattern of inheritance for a particular disorder, which can be useful in establishing a diagnosis. For example, if mental retardation is present in more than one generation in a family and only male family members are affected, an X-linked disorder should be considered. Table 47-2 reviews clues to determine patterns of inheritance. Unfortunately, limited collection of family history data, small family size, nonpaternity, delayed age of onset of symptoms, mild expression of disease symptoms, and sex-limited expression of disease symptoms (eg, a woman with a healthy father whose sisters have breast and ovarian cancer) can complicate the identification of patterns of inheritance.

Medical History “Red Flags”

In addition to family history, there are certain clinical clues derived from the patient that should alert a clinician to consider a genetic cause for a medical condition (Table 47-3). Important issues to consider in all age groups are multiple congenital anomalies, earlier-than-usual onset of common conditions, extreme pathology (eg, rare tumors or multiple primary cancers), developmental delay or degeneration, and extreme laboratory values (eg, extremely high cholesterol level).

Family medical history or clinical clues may lead a clinician to consider genetic testing. Many primary care providers may be unfamiliar with a particular genetic disorder or the availability of genetic testing for a disorder. GeneTests (http://www.genetests.org) is a web-based resource that contains concise reviews and information on genetic testing availability for many genetic disorders. This web site also provides information regarding access to genetic specialists, including medical geneticists (physicians who have residency training in genetics), genetic counselors (individuals with masters degree– level training in genetics), and PhD-qualified individuals with formal clinical genetics training.

Overview of Genetics

Human genetic information is contained in DNA and is present in nearly every cell in the human body. DNA consists of two long, paired strands of chemical bases called nucleotides. When cells divide, the DNA is compacted into complex structures composed of DNA and proteins called chromosomes; somatic cells have 46 chromosomes that are arranged in 23 pairs. The first 22 pairs, called autosomes, contain the genetic information for both men and women. The chromosomes that determine sex (X and Y) are paired as XX for females and XY for males. One chromosome from each pair is inherited from the mother and the other from the father. The germ cells or gametes (sperm and egg cells) contain only 23 chromosomes.