Chapter 064. The Practice of Genetics in Clinical Medicine (Part 1)

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Harrison's Internal Medicine Chapter 64. The Practice of Genetics in Clinical Medicine Implications of Molecular Genetics for Internal Medicine The field of medical genetics has traditionally focused on chromosomal abnormalities (Chap. 63) and Mendelian disorders (Chap. 62). 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 an illness; these genes can also influence the severity of infirmity, effect of treatment, and progression of disease. ...

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Chapter 064. The Practice of Genetics in Clinical Medicine (Part 1) Harrison's Internal Medicine > Chapter 64. The Practice of Genetics in Clinical Medicine Implications of Molecular Genetics for Internal Medicine The field of medical genetics has traditionally focused on chromosomal abnormalities (Chap. 63) and Mendelian disorders (Chap. 62). 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 an illness; these genes can
also influence the severity of infirmity, effect of treatment, and progression of disease. The primary care clinician is now faced with the role of recognizing and counseling patients at risk for a number of genetically influenced illnesses. 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 alterations are recessive and clinically silent. An even greater number, however, represent genetic variants that alter disease susceptibility, severity, 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 responses, 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. Surveys indicate that patients still turn to their primary care internist for guidance about genetic disorders, even though they may be seeing other specialists. The internist 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, as scientific advances in genetic medicine have outpaced the translation of these discoveries into standards of clinical care. Common Adult-Onset Genetic Disorders Multifactorial Inheritance 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. 62), 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. 338). Superimposed on this genetic background are environmental 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 advent of DNA-sequencing chips represents an important technical advance that promises to make large-scale testing more feasible (Chap. 62). 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 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).