Tremendous advances have been made over the past two decades in determining the molecular genetic basis for human inherited diseases. Mutations in an impressive number of genes have been linked with specific clinical conditions. Much of this work has focused on elucidating the genes associated with disorders that demonstrate Mendelian inheritance. Disorders with Mendelian inheritance are, by definition,“single-gene” disorders; that is, individuals with the mutated gene are at risk of having the disease, whereas individuals in the same kindred who do not carry the mutation are not at risk. One hope of molecular genetic diagnosis has been that it may offer the ability to predict clinical status from the genotype. However, for many of these Mendelian conditions, genotype-phenotype correlations have proved elusive (Beaudet et al. 2001; Scriver 2002). In other words, the factors that govern translation of risk for a disease, which is conferred by genotype, into phenotypic clinical disease have often remained unclear. The imprecise prediction of phenotype on the basis of the presence of a mutation is clinically apparent in the frequent occurrence of broad variability in phenotypic expression within a single family. A mutation in a gene that can either cause clinical signs or have no recognized phenotypic effect is not uncommon, and this fact is reflected in the concept of reduced penetrance. Thus, not only is the severity of disease often difficult to predict on the basis of the specific mutation but, in some cases, whether or not someone will even be affected can also be unclear. It is well recognized that for several monogenic conditions in which mutations in a single gene are believed to account for all cases of the disease (eg, cystic fibrosis