Chapter 064. The Practice of Genetics in Clinical Medicine (Part 2)

Population Screening Mass genetic screening programs require tests of high enough sensitivity and specificity to be cost-effective. An effective screening program should fulfill the following criteria: that the tested disorder is prevalent and serious; that it can be influenced presymptomatically through lifestyle changes, screening, or medications; and that identification of risk does not result in undue discrimination or harm. Screening individuals of Jewish descent for the autosomal recessive neurodegenerative disorder Tay-Sachs disease has resulted in a dramatic decline in the incidence of this syndrome in the United States. On the other hand, screening for sickle cell disease or trait...
Nội dung trích xuất từ tài liệu:
Chapter 064. The Practice of Genetics in Clinical Medicine (Part 2) Chapter 064. The Practice of Genetics in Clinical Medicine (Part 2) Population Screening Mass genetic screening programs require tests of high enough sensitivityand specificity to be cost-effective. An effective screening program should fulfillthe following criteria: that the tested disorder is prevalent and serious; that it canbe influenced presymptomatically through lifestyle changes, screening, ormedications; and that identification of risk does not result in undue discriminationor harm. Screening individuals of Jewish descent for the autosomal recessiveneurodegenerative disorder Tay-Sachs disease has resulted in a dramatic decline inthe incidence of this syndrome in the United States. On the other hand, screeningfor sickle cell disease or trait in the African-American population has sometimesresulted in insurance and employment discrimination. Mass screening for complex genetic disorders can result in potentialproblems. For example, cystic fibrosis is most commonly associated withalterations in ∆F508. This variant accounts for 30–80% of mutant allelesdepending on the ethnic group. Nevertheless, cystic fibrosis is associated withpronounced genetic heterogeneity with more than 1000 disease-related mutations.The American College of Medical Genetics recommends a panel of 23 alleles,including the ∆F508 allele, for routine diagnostic and carrier testing. Analysis forthe less common cystic fibrosis–associated mutations would greatly impact thecost of testing without significantly influencing the effectiveness of massscreening. Nevertheless, the individual who carries one of the less common cysticfibrosis–associated alterations will not benefit if testing is limited to a routinepanel. Occupational health screening programs hold promise but also raiseconcerns about employment discrimination. These concerns were brought to lightin 2001 when it was discovered that a railroad company was testing its employees,without consent, for a rare genetic condition that results in susceptibility to carpaltunnel syndrome. The Equal Employment Opportunity Commission argued thatthe tests were unlawful under the Americans with Disabilities Act. The Family History When two or more first-degree relatives are affected with asthma,cardiovascular disease, type 2 diabetes, breast cancer, colon cancer, or melanoma,the relative risk ranges from two- to fivefold, underscoring the importance offamily history for these prevalent disorders. Pending further advances in genetictesting, the key to assessing the inherited risk for common adult-onset diseasesrests in the collection and interpretation of a detailed personal and family medicalhistory in conjunction with a directed physical examination. For example, ahistory of multiple family members with early-onset coronary artery disease,glucose intolerance, and hypertension should suggest increased risk for genetic,and perhaps environmental, predisposition to metabolic syndrome (Chap. 236).Individual patients with this family history should be monitored for the possibledevelopment of hypertension, diabetes, and hyperlipidemia. They should becounseled about the importance of avoiding additional risk factors such as obesityand cigarette smoking. Family history should be recorded in the form of a pedigree. At aminimum, pedigrees should convey health-related data on all first-degree relativesand selected second-degree relatives, including grandparents. When pedigreesappear to suggest an inherited disease, they should be extended to includeadditional family members. The determination of risk for an asymptomaticindividual will vary depending on the size of the pedigree, the number ofunaffected relatives, and the types of diagnoses, as well as the ages of diseaseonset within the family. For example, a woman with two first-degree relatives withbreast cancer is at greater risk for a Mendelian disorder if she has a total of threefemale first-degree relatives than if she has a total of ten female first-degreerelatives. Additional variables that should be documented in the pedigree includethe presence or absence of nonhereditary risk factors among those affected withdiseases, and the finding of multiple diseases in an individual patient. For instance,a woman with a history of both colon cancer and endometrial cancer is at risk forhereditary nonpolyposis colon cancer (HNPCC) regardless of her family history. When assessing the personal and family history, the physician should bealert to a younger age of disease onset than is usually seen in the generalpopulation. A 30-year-old with acute myocardial infarction should be consideredat risk for a heredit ...