manifestation of complex diseases, the detection of those at high risk will identify some individuals who are more likely to benefit more from certain interventions (e.g., dietary measures in coronary heart disease). The newly acquired ability to identify some persons at high risk for certain cancers now permits more frequent monitoring for the earliest manifestations of cancer (e.g., bowel cancer). Further research and the unfolding of the Human Genome Project are very likely to reveal the underlying genes mediating predisposition to numerous common diseases, and genetic susceptibility testing will be increasingly possible. The current state of knowledge of some disorders illustrates some of the complexities of genetic testing for disorders of late onset.

Monogenic Disorders of Late Onset

Huntington Disease

The problems posed by monogenic diseases of late onset vary considerably. Huntington disease has received the most study, since indirect DNA testing has been available for nearly a decade (Gusella et al., 1983; Conneally et al., 1984; Martin and Gusella, 1986) (see Box 2-5). Indirect DNA diagnosis requires testing of an affected family member and other relatives in order to diagnose the disease in a person at risk. The identification of the genetic defect for Huntington disease as a trinucleotide expansion (Huntington's Disease Collaborative Research Group, 1993) now permits direct DNA testing and eliminates the many difficulties and the measure of uncertainty that accompanies indirect DNA testing using linkage analysis. However, since this late-onset, lethal disorder is not treatable, direct genetic testing—even without involving other family members—continues to raise many complex ethical, legal, and social issues that must be addressed through education and counseling.

Alzheimer Disease

Monogenic adult early-onset Alzheimer disease raises similar considerations to those raised by Huntington disease in that there is no effective treatment or cure (Marx, 1992). Approximately 5 percent of all cases of Alzheimer disease are transmitted as an autosomal dominant trait, and several different genes have been implicated in various families (St. George-Hyslop et al., 1990; Goate et al., 1991; Schellenberg et al., 1992), requiring a different test probe for indirect DNA testing for each of these genes. When these genes and the corresponding mutations responsible for Alzheimer disease are identified, a direct DNA test may become feasible. When a better test is developed, however, difficult decisions will still have to be made about whether, if ever, to offer testing. These dilemmas will affect many more people should predictive testing become available for the more common Alzheimer disease that starts late in life (70 to 80 years of age).

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