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Chapter 064. The Practice of Genetics in Clinical Medicine (Part 4)

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Many disorders exhibit the feature of locus heterogeneity, which refers to the fact that mutations in different genes can cause phenotypically similar disorders. For example, osteogenesis imperfecta (Chap. 357), long QT syndrome (Chap. 226), muscular dystrophy (Chap. 382), homocystinuria (Chap. 358), retinitis pigmentosa (Chap. 29), and hereditary predisposition to colon cancer (Chap. 87) or breast cancer (Chap. 86) can each be caused by mutations in distinct genes. The pattern of disease transmission, clinical course, and treatment may differ significantly, depending on the specific gene affected. In these cases, the choice of which genes to test is often determined by...

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  1. Chapter 064. The Practice of Genetics in Clinical Medicine (Part 4) Figure 64-2
  2. Many disorders exhibit the feature of locus heterogeneity, which refers to the fact that mutations in different genes can cause phenotypically similar disorders. For example, osteogenesis imperfecta (Chap. 357), long QT syndrome (Chap. 226), muscular dystrophy (Chap. 382), homocystinuria (Chap. 358), retinitis pigmentosa (Chap. 29), and hereditary predisposition to colon cancer (Chap. 87) or breast cancer (Chap. 86) can each be caused by mutations in distinct genes. The pattern of disease transmission, clinical course, and treatment may differ significantly, depending on the specific gene affected. In these cases, the choice of which genes to test is often determined by unique clinical and family history features, the relative prevalence of mutations in various genes, or test availability. Methodologic Approaches to Genetic Testing Genetic testing is performed in much the same way as other specialized laboratory tests. In the United States, genetic testing laboratories are CLIA (Clinical Laboratory Improvement Act) approved to ensure that they meet quality and proficiency standards. A useful source for various genetic tests is www.genetests.org. DNA testing is most commonly performed by DNA sequence analysis for mutations, although genotype can also be deduced through the study of RNA or protein (e.g., apoprotein E, hemoglobin, immunohistochemistry). The
  3. determination of DNA sequence alterations relies heavily on the use of polymerase chain reaction (PCR), which allows rapid amplification and analysis of the gene of interest. In addition, PCR enables genetic testing on minimal amounts of DNA extracted from a wide range of tissue sources including leukocytes, fibroblasts, epithelial cells in saliva or hair, and archival tissues. Amplified DNA can be analyzed directly by DNA sequencing or it can be hybridized to DNA chips or blots to detect the presence of normal and mutant DNA sequences. Direct DNA sequencing is increasingly used for prenatal diagnosis as well as for determination of hereditary disease susceptibility. Analyses of large alterations in the genome are possible using cytogenetics, fluorescent in situ hybridization (FISH), or Southern blotting (Chap. 63). Protein truncation tests (PTTs) are used to detect mutations that result in the premature termination of a polypeptide occurring during protein synthesis. In this assay, the isolated complementary DNA (cDNA) is transcribed and translated in vitro, and the protein is analyzed by gel electrophoresis. The truncated (mutant) gene product is readily identified as its electrophoretic mobility differs from that of the normal protein. This test is used most commonly for analyses of large genes with significant genetic heterogeneity such as DMD, APC, and the BRCA genes. Like all laboratory tests, there are limitations to the accuracy and interpretation of genetic tests. In addition to technical errors, genetic tests are sometimes designed to detect only the most common mutations. In this case, a
  4. negative result must be qualified by the possibility that the individual may have a mutation that is not included in the test. In addition, a negative result does not mean that there is not a mutation in some other gene that causes a similar inherited disorder. In addition to molecular testing for established disease, genetic testing for susceptibility to chronic disease is being increasingly integrated into the practice of medicine. In most cases, however, the discovery of disease-associated genes has greatly outpaced studies that assess clinical outcomes and the impact of interventions. Until such evidence-based studies are available, predictive molecular testing must be approached with caution and should be offered only to patients who have been adequately counseled and have provided informed consent. In the majority of cases, genetic testing should be offered only to individuals with a suggestive personal or family medical history or in the context of a clinical trial. Predictive genetic testing falls into two distinct categories. Presymptomatic testing applies to diseases where a specific genetic alteration is associated with a near 100% likelihood of developing disease. In contrast, predisposition testing predicts a risk for disease that is less than 100%. For example, presymptomatic testing is available for those at risk for Huntington's disease, whereas predisposition testing is considered for those at risk for hereditary breast cancer. It is important to note that, for the majority of adult-onset, multifactorial genetic
  5. disorders, testing is purely predictive. Test results cannot reveal with confidence whether, when, or how the disease will manifest itself. For example, not everyone with the apolipoprotein E allele (ε4) will develop Alzheimer's disease, and individuals without this genetic marker can still develop the disorder (Chap. 365).
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