During the 20th century it became apparent to geneticists that chromosomes (the structures that package the genes) could be mutated independently of the genes themselves. Any cytogenetic condition, that is, a genetic disease caused solely by the rearrangement of whole or parts of chromosomes, came to be called a major chromosome anomaly (MCA). Among the better-known examples of MCAs are Down syndrome (trisomy 21), Turner syndrome (monosomy X), Klinefelter syndrome (XXY aneuploidy), and Cri-du-chat syndrome (5del) (see Table 1 of the entry Genetic Disease II).
Chromosomal Mutations. These include changes in chromosomes that are either numerical (too many or too few chromosomes, causing aneuploidy) or structural (the translocation or repatterning of portions of chromosomes). A standard karyotype for each species, including humans, is used for comparison. Among the more common modes of chromosome mutations are deletions, fusions, dissociations (fissions), inversions, and translocations. Many MCAs can profoundly influence phenotypic features. In the 1860s, Dr. John Langdon Haydon Down identified a striking phenotype that he called Mongolism, later renamed Down syndrome.4
The causal mechanism of Down syndrome was characterized in 1959 as a failure of homologous chromatids to separate normally during meiosis (non-disjunction), resulting in a fetus with three copies of a chromosome, now termed trisomy (in this case, trisomy-21).
The probability of experiencing certain chromosome mutations such as Down syndrome can be a function of maternal age. This change in probability is known in general as an advanced parental age effect, and is significant for some chromosome mutations that cause congenital genetic diseases after the mother reaches about age 35. The probability of having dizygotic twins also increases in frequency with advancing maternal age.
Researchers soon described other MCAs that involve whole or large portions of chromosomes: the Philadelphia chromosome (a balanced translocation), Edward syndrome (trisomy 18), Patau syndrome (trisomy 13), triplo-Xsyndrome (XXX aneuploidy), and double-Ysyndrome (XYY aneuploidy). As cytogenetic techniques improved, many additional MCAs were identified in humans, involving mechanisms such as Robertsonsonian translocations, inversions, duplications, and deletions.
Cytogenetic irregularities are responsible for roughly one half of all naturally terminated pregnancies.5 Nature thus seems to eliminate most cytogenetic mutations; still, 1% of all live-born children possess a congenital cytogenetic disease.
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