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

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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Chapter 064. The Practice of Genetics in Clinical Medicine (Part 4) Chapter 064. The Practice of Genetics in Clinical Medicine (Part 4)Figure 64-2 Many disorders exhibit the feature of locus heterogeneity, which refers tothe fact that mutations in different genes can cause phenotypically similardisorders. 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 distinctgenes. The pattern of disease transmission, clinical course, and treatment maydiffer significantly, depending on the specific gene affected. In these cases, thechoice of which genes to test is often determined by unique clinical and familyhistory features, the relative prevalence of mutations in various genes, or testavailability. Methodologic Approaches to Genetic Testing Genetic testing is performed in much the same way as other specializedlaboratory tests. In the United States, genetic testing laboratories are CLIA(Clinical Laboratory Improvement Act) approved to ensure that they meet qualityand proficiency standards. A useful source for various genetic tests iswww.genetests.org. DNA testing is most commonly performed by DNA sequence analysis formutations, although genotype can also be deduced through the study of RNA orprotein (e.g., apoprotein E, hemoglobin, immunohistochemistry). Thedetermination of DNA sequence alterations relies heavily on the use ofpolymerase chain reaction (PCR), which allows rapid amplification and analysisof the gene of interest. In addition, PCR enables genetic testing on minimalamounts of DNA extracted from a wide range of tissue sources includingleukocytes, fibroblasts, epithelial cells in saliva or hair, and archival tissues.Amplified DNA can be analyzed directly by DNA sequencing or it can behybridized to DNA chips or blots to detect the presence of normal and mutantDNA sequences. Direct DNA sequencing is increasingly used for prenataldiagnosis 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 inthe premature termination of a polypeptide occurring during protein synthesis. Inthis assay, the isolated complementary DNA (cDNA) is transcribed and translatedin vitro, and the protein is analyzed by gel electrophoresis. The truncated (mutant)gene product is readily identified as its electrophoretic mobility differs from thatof the normal protein. This test is used most commonly for analyses of large geneswith significant genetic heterogeneity such as DMD, APC, and the BRCA genes. Like all laboratory tests, there are limitations to the accuracy andinterpretation of genetic tests. In addition to technical errors, genetic tests aresometimes designed to detect only the most common mutations. In this case, anegative result must be qualified by the possibility that the individual may have amutation that is not included in the test. In addition, a negative result does notmean that there is not a mutation in some other gene that causes a similar inheriteddisorder. In addition to molecular testing for established disease, genetic testing forsusceptibility to chronic disease is being increasingly integrated into the practiceof medicine. In most cases, however, the discovery of disease-associated genes hasgreatly outpaced studies that assess clinical outcomes and the impact ofinterventions. Until such evidence-based studies are available, predictivemolecular testing must be approached with caution and should be offered only topatients who have been adequately counseled and have provided informedconsent. In the majority of cases, genetic testing should be offered only toindividuals with a suggestive personal or family medical history or in the contextof a clinical trial. Predictive genetic testing falls into two distinct categories. Presymptomatictesting applies to diseases where a specific genetic alteration is associated with anear 100% likelihood of developing disease. In contrast, predisposition testingpredicts a risk for disease that is less than 100%. For example, presymptomatictesting is available for those at risk for Huntingtons disease, whereaspredisposition testing is considered for those at risk for hereditary breast cancer. Itis important to note that, for the majority of adult-onset, multifactorial geneticdisorders, testing is purely predictive. Test results cannot reveal with conf ...