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

Harrisons Internal Medicine Chapter 64. The Practice of Genetics in Clinical MedicineImplications of Molecular Genetics for Internal MedicineThe 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, Alzheimers 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 canalso 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) Chapter 064. The Practice of Genetics in Clinical Medicine (Part 1) Harrisons Internal Medicine > Chapter 64. The Practice of Genetics inClinical Medicine Implications of Molecular Genetics for Internal Medicine The field of medical genetics has traditionally focused on chromosomalabnormalities (Chap. 63) and Mendelian disorders (Chap. 62). However, there isgenetic susceptibility to many common adult-onset diseases, includingatherosclerosis, cardiac disorders, asthma, hypertension, autoimmune diseases,diabetes mellitus, macular degeneration, Alzheimers disease, psychiatricdisorders, and many forms of cancer. Genetic contributions to these commondisorders involve more than the ultimate expression of an illness; these genes canalso influence the severity of infirmity, effect of treatment, and progression ofdisease. The primary care clinician is now faced with the role of recognizing andcounseling patients at risk for a number of genetically influenced illnesses. Amongthe greater than 20,000 genes in the human genome, it is estimated that each of usharbors several potentially deleterious mutations. Fortunately, many of thesealterations are recessive and clinically silent. An even greater number, however,represent genetic variants that alter disease susceptibility, severity, or response totherapy. Genetic medicine is changing the way diseases are classified, enhancing ourunderstanding of pathophysiology, providing practical information concerningdrug metabolism and therapeutic responses, and allowing for individualizedscreening and health care management programs. In view of these changes, the physician must integrate personal medicalhistory, family history, and diagnostic molecular testing into the overall care ofindividual patients and their families. Surveys indicate that patients still turn totheir primary care internist for guidance about genetic disorders, even though theymay be seeing other specialists. The internist has an important role in educating patients about theindications, benefits, risks, and limitations of genetic testing in the management ofa number of diverse diseases. This is a difficult task, as scientific advances ingenetic medicine have outpaced the translation of these discoveries into standardsof clinical care. Common Adult-Onset Genetic Disorders Multifactorial Inheritance The risk for many adult-onset disorders reflects the combined effects ofgenetic factors at multiple loci that may function independently or in combinationwith other genes or environmental factors. Our understanding of the genetic basisof these disorders is incomplete, despite the clear recognition of geneticsusceptibility. In type 2 diabetes mellitus, for example, the concordance rate inmonozygotic twins ranges between 50 and 90%. Diabetes or impaired glucosetolerance occurs in 40% of siblings and in 30% of the offspring of an affectedindividual. Despite the fact that diabetes affects 5% of the population and exhibits ahigh 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. Theyinclude certain mitochondrial DNA disorders (Chap. 62), mutations in a cascadeof 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 environmentalinfluences such as diet, exercise, pregnancy, and medications. Identifying susceptibility genes associated with multifactorial adult-onsetdisorders is a formidable task. Nonetheless, a reasonable goal for these types ofdiseases is to identify genes that increase (or decrease) disease risk by a factor oftwo or more. For common diseases such as diabetes or heart disease, this level of riskhas important implications for health. In much the same way that cholesterol iscurrently used as a biochemical marker of cardiovascular risk, we can anticipatethe development of genetic panels with similar predictive power. The advent ofDNA-sequencing chips represents an important technical advance that promises tomake large-scale testing more feasible (Chap. 62). Whether to perform a genetic test for a particular inherited adult-onsetdisorder, such as hemochromatosis, multiple endocrine neoplasia (MEN) type 1,prolonged QT syndrome, or Huntington disease, is a complex decision; it dependson the clinical features of the disorder, the desires of the patient and family, andwhether the results of genetic testing will alter medical decision-making ortreatme ...