Genetic Susceptibility to Birth Defects in Humans:

ADVANCES IN HUMAN GENETIC RESEARCH With the relentless progress of the Human Genome Project, by the year 2001, most-if not all-of the estimated 100,000 human genes will have been found (Collins, '98). Close to 10,000 genes have already been cataloged (Online Mendelian Inheritance in Man, '98), and tests for more than 700 genes are already available in medical practice (Pagon, '98). The genes identified thus far range from those associated with rare metabolic disorders to those associated with common diseases including cancer and adult-onset conditions. Genetic variants confer increased susceptibility to a variety of environmental factors (including chemical, infectious, physical, social, psychological, be-havioral, and nutritional factors), thus increasing the risk of carriers for many diseases including birth defects. Although birth defects remain the leading cause of infant mortality in the United States (CDC, '98), the causes of most birth defects remain elusive. Nevertheless, an increasing number of clinical and epidemiologic studies are beginning to identify risk factors for birth defects (Khoury, '95). Over the last two decades , numerous investigators have identified malformations associated with rare single-gene disorders. Table 1 shows the results of a quick search of the Online Mendelian Inheritance in Man Catalog on the Internet. As can be seen, dozens of genes (mostly in a few families) have been reported to be associated with a variety birth defects leading to malformation syndromes. Increasingly, more common gene variants have been associated with the risk for common birth defects. For example, the me-thylene tetrahydrofolate reductase (MTHFR) polymorphism has been associated with the risk for neural tube defects (Posey, '96). The interaction between gene variants at multiple loci with environmental exposures is likely to explain most common defects such as neural tube defects, oral clefts, and congenital car-diovascular malformations. As a result of genetic research, information on differential genetic susceptibility to birth defects will be accumulating. Ideally, information on genetic susceptibility to birth defects will be used to target beneficial interventions that reduce the risk for birth defects (e.g., nutritional interventions such as folic acid), or to avoid certain pregnancy exposures for individuals at greatest risk (e.g., avoiding certain anti-epileptic drugs on the basis of a person's genetic metabolic profile). However, complex ethical, legal, and social issues are already being raised about the pitfalls of genetic testing in general (Lewontin, '96). The effective use of genetic knowledge and technology is becoming a crucial challenge to the public health community. The …