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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. | Chapter 064. The Practice of Genetics in Clinical Medicine Part 4 Figure 64-2 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 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