developmental defects. The majority of adverse pregnancy outcomes in humans are of unknown etiology and are viewed as complex traits in which exogenous agents might interact with particular combinations of allelic variants of genes controlling development and differentiation to produce adverse pregnancy outcomes. Studies of gene-environment interactions during embryogenesis and fetal development have become commonplace and increasingly appreciated. Categories of disease etiology can be viewed as spanning the range from totally genetic in causation to totally environmental in causation. These categories include single gene causation, chromosomal causation, multifactorial causation with high heritability, multifactorial causation with low heritability, infectious causes, and environmental causes (Khoury et al. 1993a).
Many single-gene disorders are characterized by a low frequency of the disease allele in the general population (allelic frequency, 1% or less) and high penetrance (a high proportion of individuals with the disease allele develop the disorder). Susceptibility genes for these single-gene disorders typically demonstrate Mendelian patterns of inheritance and are associated with high disease risk. Although individually rare, single-gene Mendelian disorders contribute significantly to infant morbidity and mortality. Approximately 4-7% of pediatric hospital admissions are made for recognized Mendelian diseases (Khoury et al. 1993b). From more than 2,000 likely single-gene developmental-defect syndromes in humans, the gene has been isolated and mapped for 100 of these syndromes and mapped but not yet isolated for another 100 (Winter 1996). In the mouse, for comparison, there are approximately 500 spontaneously occurring single-gene defects associated with developmental defects. Approximately 75 of these genes have been isolated, and greater than 400 have been mapped (Winter 1996). Furthermore, more than 1,000 mouse mutants have been prepared with known gene defects (many in components of signaling pathways), and many of these have phenotypes that fully qualify them as mouse single-gene developmental defects. Despite the availability of mouse mutants and the identification of genes important in development of C. elegans, Drosophila, and zebrafish (see Chapters 6 and 7), the study of single-gene defects contributing to developmental defects in humans has not yet received much experimental attention. Genes identified as important for development in C. elegans, Drosophila, and zebrafish, however, provide a rich source of information for identification of potential susceptibility genes in humans. That strikes this committee as an underutilized resource.
Multifactorial disorders, or complex diseases, are characterized by genetic complexity and probable gene-environment interactions (Ellsworth et al. 1997). These diseases tend to aggregate within families but are not inherited in simple Mendelian fashion. They are typically found in a higher proportion within affected families than expected in the general population. In contrast to single-gene disorders, susceptibility genes for complex disorders tend to be common in the population (allelic frequency more than 1%) and can be considered polymorphisms. Susceptibility genes are usually associated with low risk to the indi-