The consequences of chromosome imbalance.

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.(ABSTRACT TRUNCATED AT 250 WORDS)