Chromosome abnormalities are responsible for a significant proportion of genetic disorders that appear to arise de novo. On average chromosome abnormalities occur in 1/150 live births and are the leading cause of mental retardation, as well as spontaneous abortion in the first and second-trimester of pregnancy (in 50% and 20% of cases, respectively) (JORDE et al., 1999). These abnormalities may involve several genes on one or more chromosomes and consequently, the phenotypic characteristics of a chromosomal disorder often resemble polygenic or pleiotropic diseases. For example, many chromosome disorders are associated with some form of mental retardation, in addition to congenital malformations (especially heart defects), growth delay, and very characteristic facial morphogenesis. The diagnosis of most chromosomal abnormalities can now be made during pregnancy through amniocentesis and cytogenetic analysis.
Using chromosome banding techniques and fluorescent in situ hybridization analysis, cytogenetics can determine changes in chromosome structure at a resolution of 1-10 Mb. These abnormalities include rearrangements within a given chromosome (i.e., deletions, insertions, duplications, and inversions) or between chromosomes (i.e., translocations), as well as changes in chromosome number or ploidy. Chromosome abnormalities also allow the rapid assignment of a genetic component to any disorder that is consistently associated with chromosome rearrangements or ploidy changes. For example, genes located at the breakpoints in chromosomal translocations are sometimes directly implicated in causing the disease. Thus, chromosomal rearrangements are the “smoking guns” of genetics, implicating a gene or genes in the etiology of a genetic disorder.
Chromosome abnormalities can be present in every cell of an individual (constitutional abnormality), or may be present in only certain tissues (somatic or acquired abnormality) (JORDEet al., 1999).Somatic abnormalities can be separated into two broad classes: mosaicism, in which an individual possesses two or more genetically different subsets of cells derived from the same zygote, and chimerism, in which an individual possesses two or more genetically different subsets of cells that are derived from different zygotes. Often abnormalities that would be lethal in constitutional form, such as most trisomies, can result in viable embryos when present as chimeras or mosaics with genetically normal cells. Chimerism and mosaicism are often discovered during routine blood analysis, and aneuploidy mosaics are very common.