The field of medical genetics has traditionally focused on chromosomal abnormalities (Chap. 62) and Mendelian disorders (Chap. 61). However, there is genetic susceptibility to many common adult-onset diseases, including atherosclerosis, cardiac disorders, asthma, hypertension, autoimmune diseases, diabetes mellitus, macular degeneration, Alzheimer's disease, psychiatric disorders, and many forms of cancer. Genetic contributions to these common disorders involve more than the ultimate expression of the condition; these genes can also influence the severity of illness, progression of disease, and effect of treatment.
The primary care clinician is now faced with the role of recognizing and counseling patients at risk for a number of genetically influenced diseases. Among the greater than 20,000 genes in the human genome, it is estimated that each of us harbors several potentially deleterious mutations. Fortunately, many of these genetic alterations are recessive or clinically silent. An even greater number, however, represent genetic variants that alter disease susceptibility, course, or response to therapy.
Genetic medicine is changing the way diseases are classified, enhancing our understanding of pathophysiology, providing practical information concerning drug metabolism and therapeutic response, and allowing for individualized screening and health care management programs. In view of these changes, the physician must integrate personal medical history, family history, and diagnostic molecular testing into the overall care of individual patients and their families. Patients turn to their primary care providers for guidance about genetic disorders, even though they may also be seeing other specialists. The primary care provider has an important role in educating patients about the indications, benefits, risks, and limitations of genetic testing in the management of a number of diverse diseases. This is a difficult task, because scientific advances in genetic medicine are outpacing the translation of these discoveries into standards of clinical care.
The risk for many adult-onset disorders reflects the combined effects of genetic factors at multiple loci that may function independently or in combination with other genes or environmental factors. Our understanding of the genetic basis of these disorders is incomplete, despite the clear recognition of genetic susceptibility. In Type 2 diabetes mellitus, for example, the concordance rate in monozygotic twins ranges between 50 and 90%. Diabetes or impaired glucose tolerance occurs in 40% of siblings and in 30% of the offspring of an affected individual. Despite the fact that diabetes affects 5% of the population and exhibits a high degree of heritability, only a few genetic mutations (most of which are rare) that might account for the familial nature of the disease have been identified. They include certain mitochondrial DNA disorders (Chap. 61), mutations in a cascade of genes that control pancreatic islet cell development and function (HNF4α, HNF1α, IPF1, TCF7L2, glucokinase), insulin receptor mutations, and others (Chap. 344). In addition to these known genes, a large number of additional genetic loci that confer disease susceptibility have been identified. Superimposed on this genetic background are environmental or medical influences such as diet, exercise, pregnancy, and medications.
Identifying susceptibility genes associated with multifactorial adult-onset disorders is a formidable task. Nonetheless, a reasonable goal for these types of diseases is to identify genes that increase (or decrease) disease risk by a factor of two or more. For common diseases such as diabetes or heart disease, this level of risk has important implications for health. In much the same way that cholesterol is currently used as a biochemical marker of cardiovascular risk, we can anticipate the development of genetic panels with similar predictive power. The availability of DNA-microarray systems represents an important technology that makes large-scale testing feasible (Chap. 61). Whether to perform a genetic test for a particular inherited adult-onset disorder, such as hemochromatosis, multiple endocrine neoplasia (MEN) type 1, prolonged QT syndrome, or Huntington's disease, is a complex decision; it depends on the clinical features of the disorder, the desires of the patient and family, and whether the results of genetic testing will alter medical decision-making or treatment (see below).
Mass genetic screening programs require tests with high enough sensitivity and specificity to be cost-effective. An effective screening program should fulfill the following criteria: the tested disorder is prevalent and serious; it can be influenced presymptomatically through lifestyle changes, screening, medications, or other risk-reducing interventions; and identification of risk does not result in undue discrimination or harm. Screening individuals of Jewish descent for the autosomal recessive neurodegenerative disorder Tay-Sachs disease has resulted in a dramatic decline in the incidence of this syndrome in the United States. On the other hand, screening for sickle cell disease or trait in the African-American population has sometimes resulted in insurance and employment discrimination.
Mass screening for complex genetic disorders can result in potential problems. For example, cystic fibrosis is most commonly associated with the ΔF508 mutation. This variant accounts for 30–80% of mutant alleles, depending on the ethnic group. Nevertheless, cystic fibrosis is associated with pronounced genetic heterogeneity with more than 1000 disease-related mutations. The American College of Medical Genetics recommends a panel of 23 alleles, including the ΔF508 allele, for routine carrier testing. Analysis for the less common cystic fibrosis–associated mutations would greatly impact the cost of testing without significantly influencing the effectiveness of mass screening. Nevertheless, the individual who carries one of the less common cystic fibrosis–associated alterations will not benefit if testing is limited to a routine panel.
Occupational health screening programs hold promise but also raise concerns about employment discrimination. These concerns were brought to light when it was discovered that a railroad company was testing its employees, without consent, for a rare genetic condition that results in susceptibility to carpal tunnel syndrome. The Equal Employment Opportunity Commission argued that the tests were unlawful under the Americans with Disabilities Act.