Chapter 064. The Practice of Genetics in Clinical Medicine (Part 8)

Preventive measures and therapeutic interventions are not restricted to metabolic disorders. Identification of familial forms of long QT syndrome, associated with ventricular arrhythmias, allows early electrocardiographic testing and the use of prophylactic antiarrhythmic therapy, overdrive pacemakers, or defibrillators (Chap. 226). Individuals with familial hypertrophic cardiomyopathy can be screened by ultrasound, treated with beta blockers or other drugs, and counseled about the importance of avoiding strenuous exercise and dehydration (Chap. 231). Likewise, individuals with Marfan syndrome can be treated with beta blockers and monitored for the development of aortic aneurysms (Chap. 242). ...
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Chapter 064. The Practice of Genetics in Clinical Medicine (Part 8) Chapter 064. The Practice of Genetics in Clinical Medicine (Part 8) Preventive measures and therapeutic interventions are not restricted tometabolic disorders. Identification of familial forms of long QT syndrome,associated with ventricular arrhythmias, allows early electrocardiographic testingand the use of prophylactic antiarrhythmic therapy, overdrive pacemakers, ordefibrillators (Chap. 226). Individuals with familial hypertrophic cardiomyopathycan be screened by ultrasound, treated with beta blockers or other drugs, andcounseled about the importance of avoiding strenuous exercise and dehydration(Chap. 231). Likewise, individuals with Marfan syndrome can be treated with betablockers and monitored for the development of aortic aneurysms (Chap. 242).Individuals with α1 antitrypsin deficiency can be strongly counseled to avoidcigarette smoking and exposure to environmental pulmonary and hepatotoxins.Various host genes influence the pathogenesis of certain infectious diseases inhumans, including HIV (Chap. 182). The factor V Leiden allele increases risk ofthrombosis (Chap. 59). Approximately 3% of the worldwide population isheterozygous for this mutation. Moreover, it is found in up to 25% of patients withrecurrent deep-vein thrombosis or pulmonary embolism. Women who areheterozygous or homozygous for this allele should therefore avoid the use of oralcontraceptives and receive heparin prophylaxis after surgery or trauma. The field of pharmacogenomics seeks to identify genes that alter drugmetabolism or confer susceptibility to toxic drug reactions. Pharmacogenomicspermits individualized drug therapy, resulting in improved treatment outcomes,reduced toxicities, and more cost-effective pharmaceutical care. Examples includesuccinylcholine sensitivity, thiopurine methyltransferase (TPMT) deficiency,malignant hyperthermia, dihydropyrimidine dehydrogenase deficiency, theporphyrias, and glucose-6-phosphase dehydrogenase (G6PD) deficiency. As noted above, the identification of genes that increase the risk of specifictypes of neoplasia is rapidly changing the management of many cancers.Identifying family members with mutations that predispose to FAP or hereditarynonpolyposis colon cancer (HNPCC) can lead to recommendations of early cancerscreening or prophylactic surgery (Chap. 87). Similar principles apply to familialforms of melanoma, basal cell carcinoma, and cancers of the breast, ovary, andthyroid gland. It should be recognized, however, that most cancers harbor severaldistinct genetic abnormalities by the time they acquire invasive or metastaticpotential (Chaps. 79 and 80). Consequently, the major impact of genetic testing inthese cases is to allow more intensive clinical screening, as it remains verychallenging to predict disease penetrance, expression, or clinical course. Although genetic diagnosis of these and other disorders is only beginningto be used in the clinical setting, predictive testing holds the promise of allowingearlier and more targeted interventions that can reduce morbidity and mortality.We can expect the availability of genetic tests to expand. A critical challenge forphysicians and other health care providers is to keep pace with these advances ingenetic medicine and to implement testing judiciously. Further Readings Clayton EW: Ethical, legal, and social implications of genomic medicine. NEngl J Med 349:562, 2003 [PMID: 12904522] Collins FS, Watson JD: Genetic discrimination: Time to act. Science302:745, 2003 [PMID: 14593134] Ensenauer RE: Genetic testing: Practical, ethical, and counselingconsiderations. Mayo Clin Proc 80:63, 2005 [PMID: 15667031] Guttmacher AE, Collins FS: Genomic medicine—a primer. N Engl J Med347:1512, 2002 [PMID: 12421895] Harper PS: Practical Genetic Counselling, 5th ed. Oxford, ButterworthHeinmann, 1998 McCandless SE et al: The burden of genetic disease on inpatient care in achildrens hospital. Am J Hum Genet 74:121, 2004 [PMID: 14681831] Wolfberg AJ: Genes on the web—Direct-to-consumer marketing of genetictesting. N Engl J Med 355:543, 2006 [PMID: 16899772]