Multiple hits during early embryonic development: digenic diseases and holoprosencephaly.

Multiple genetic and environmental factors likely play a role in the phenotypic expression of many Mendelian disorders. Understanding the biologic role of the genes associated with human disease may guide future explorations of additional modifier genes. For example, with HPE, there are several possible categories of additional candidate genes and potential sites of interaction. First, there are genes encoding proteins that are in the signaling pathways for identified disease genes (e.g., Shh and nodal signaling). Second, genes involved in the relevant developmental processes are potential candidate genes for human diseases (dorsal-ventral patterning of the forebrain, other processes in midline forebrain development, prechordal mesoderm induction). Third, genes involved in synthesis or metabolism of teratogenic agents (cholesterol biosynthesis, retinoic acid metabolism) could also be potential genetic contributors. Multiple genetic hits or environmental exposures may be required for clinical expression of many Mendelian disorders. Conceptions of a disease being the result of mutations in a single gene should take into account the overlap between Mendelian and multifactorial disorders. Indeed, as more detail emerges demonstrating the impact of genomic and environmental variability on phenotype, we may reconceptualize classic Mendelian and complex multifactorial disorders as two ends of a continuum of disease causation, with the gradient reflecting the relative independence of a given mutation in producing the disease phenotype. It may be useful to remember that “genomes speak biochemistry, not phenotype” (Plasterk 1999). Future studies will focus both on the identification of additional genes involved with these human diseases and on the understanding of their biologic interactions. Such information will lend greater insight into the complex genetic and environmental influences that lead to phenotypic expression of a trait.