The consequences of chromosome imbalance

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Abstract
Review of the clinical cytogenetic literature provides compelling evidence for a specific relationship between imbalance of particular chromosomes or chromosomal regions and the appearance of defined patterns of phenotypic abnormalities. In many instances, detailed phenotypic mapping has made it possible to assign portions of a phenotype to relatively small chromosome segments, which are sometimes referred to as “critical regions.” However, since these regions are usually defined by a subset of the phenotypic manifestations of an aneuploidy syndrome—generally those anomalies that are regarded as most characteristic or readily observable—it is important not to fall into the trap of thinking that it is imbalance of only these regions that has deleterious effects on development and function. Thus, in Down syndrome, the presence of an extra copy of the proximal part of 21q22.3 appears to result in the typical physical phenotype—as defined principally in terms of the characteristic facial and hand anomalies and congenital heart defect—in addition to mental retardation. But, duplication of proximal 21q also affects mental development, and the regions responsible for many other aspects of the Down syndrome phenotype, including Alzheimer disease, have not been defined at all. Therefore, it remains likely that loci present on many parts of the long arm of chromosome 21 play a role in the development of the overall phenotype of Down syndrome. The immediate effect at the molecular level of an aneuploidy‐caused alteration in gene dose appears to be a non‐compensated commensurate change in the production of gene products. Therefore, the mechanisms invoked to explain the genesis of the phenotype must be based on 50% increases and decreases in gene product synthesis in trisomies and monosomies, respectively. Despite the specificity of patterns of phenotypic abnormalities, there is both a considerable degree of variability in the expression of the individual components that constitute these patterns and a significant degree of overlap among the patterns of different aneuploid states. This variability is presumed to be the result of a combination of stochastic, environmental, and other genetic factors which impinge on but do not obscure the overall pattern of abnormalities. The overlap of phenotypes may be attributable to the involvement of many gene products of different chromosomal origin in any particular developmental pathway, and hence the susceptibility of such pathways to a variety of perturbations.