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 ...