identical phenotype, as is the case for retinitis pigmentosa, an inherited form of blindness. Another form of heterogeneity, allelic heterogeneity, is caused by different mutations in a single gene that give rise to manifestations of a disease. In the case of CF, more than 300 mutations have been found in the same gene. To complicate matters further, a mutation that expresses itself clinically in one person may produce no detectable effect in another (reduced penetrance) or, if it does appear, it may have a wide range of symptomatology or severity (variable expressivity). Both of these phenomena may be due to other genes that ameliorate the effect of the mutated gene.

Some genetic conditions do not manifest clinically until adulthood and may only become apparent in middle age or later. Predictive testing aims at predicting diseases before they are clinically expressed. Although some monogenic disorders of late onset are not particularly rare (e.g., polycystic kidney disease, hemochromatosis), they do not make up a large fraction of the disease load of the population. In contrast, common diseases of more complex etiology that include genetic factors comprise the bulk of diseases producing ill health.

We are learning that many common diseases may be due to the presence of a variable number of susceptibility genes. Thus, in coronary heart disease, a yet-unknown number of genes related to fat and cholesterol metabolism, clotting susceptibility, and other effects, interacts with environmental factors such as smoking and diet, to lead to the clinical end result. The relative contribution of genes and environment varies between individuals and families. This general pattern of interaction between heredity and environment appears to apply to many common diseases such as hypertension, diabetes, and allergies. Such conditions are not commonly considered genetic diseases, but genetic factors are thought to play a significant role in their development. Since elucidation of various genetic factors can often detect those at greatest risk, genetic testing for susceptibility might be useful in identifying groups of persons who could benefit from appropriate preventive measures. Understanding the genetic components of these disorders may lead to the development of new therapies as well.

In addition to the classical patterns of monogenic and multifactorial inheritance, several novel mechanisms of inheritance have been described in recent years. The severity and nature of the disease may depend on which parent provided the faulty gene. This phenomenon, called genomic imprinting, has recently been detected in rare disorders and is currently under intensive study. In uniparental disomy, both members of a chromosomal pair are transmitted from one parent (instead of the one chromosome that would ordinarily be transmitted from each parent); this rare event allows a recessive disorder to be expressed in a child when only one parent is a carrier for the mutant gene.

In another recent development, research has focused on the diseases resulting from the DNA transmission of mitochondrial disorders. Mitochondria are energy-generating organelles (components inside the cytoplasm of every cell) and carry their own chromosomal DNA. They are thought to be descendants of an-

The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement