The clinical presentation of DS is complex and variable. A few features occur to some degree in every individual with trisomy 21, including characteristic facial dysmorphology, a small and hypocellular brain, and the histopathology of Alzheimer disease, which is present by the fourth decade. Individuals with DS are invariably cognitively impaired, though the severity is highly variable. Hypotonia occurs frequently in newborns, and most have atypical dermatoglyphic features, though the specific subset of these is again individually variable.
Trisomy 21 is also a risk factor for a number of diseases. For example, it is among the leading causes of congenital heart disease (CHD), some form of which occurs in 40%–50% of those with DS [4
]. The incidence of childhood onset leukemia and Hirschsprung disease are both significantly elevated in individuals with trisomy 21. Health-care guidelines for individuals with DS include more than 80 clinical features that occur more frequently than in the population at large [5
]. Three critical points for this discussion arise from these basic observations: (1) the incidence of most phenotypes seen in DS is variable; (2) the severity of a given feature is highly variable; and (3) none of the features diagnosed in DS is unique to people with trisomy 21. For “DS features” that also occur in euploid individuals, we assume that there is some commonality of etiology regardless of ploidy, but this must be proven for any specific case.
A central challenge of genetic research in humans is to precisely define phenotype. This is especially critical in DS, which is a product of genetic effects on different cells, structures, and functions throughout development, many of which may have cascading effects to produce clinically observed phenotypic end points in a given individual with trisomy 21 [6
]. A first step in this process is to separate those effects of trisomy that disturb development from those that alter function of cells that have reached an end point of differentiation. These are obviously not independent concepts; any “developmental” perturbation derives from alteration of some function in a developing cell. However, understanding when trisomy causes a divergence from normal patterns of development in a cell that exists only for a defined period during embryogenesis requires a different experimental approach (and, ultimately, a different therapeutic approach) than measuring how trisomy affects a steady-state function (e.g., a signaling or metabolic pathway, neuronal response to stimulation, etc.) in a terminally differentiated cell. Indeed, the altered functions of a mature cell may have little or nothing to do with up-regulation of trisomic genes in that cell, but rather could reflect a developmental error caused by trisomy that has downstream consequences that affect function. That is, a specific phenotype may be a consequence
of but not a direct product
of trisomic gene expression (developmental versus functional effects).