pediatrics
Down Syndrome (Trisomy 21)
Etiology of Down Syndrome
In approximately 95% of cases, Down syndrome is caused by nondisjunction resulting in an extra chromosome 21 (trisomy 21), which is typically maternally derived ( Etiology references ). Such people have 47 chromosomes instead of the normal 46. Approximately 4% of Down syndrome cases are due to a translocation ( Etiology references ). In a balanced translocation, genetic material is exchanged with material from another nonhomologous chromosome, and the chromosome count is maintained at 46. The most common translocation is t(14;21), in which chromosome 21 is attached to chromosome 14; this is an unbalanced translocation, resulting in a chromosome count of 45. In about half of people with the t(14;21) translocation, both parents have normal karyotypes, indicating a de novo translocation. In the other half, one parent (almost always the mother), who does not have Down syndrome, has only 45 chromosomes, one of which is t(14;21). Theoretically, the chance that a carrier mother will have a child with Down syndrome is 1:3, but the actual risk is lower (approximately 1:10). If the father is the carrier, the risk is only 1:20. The next most common translocation is t(21;22). In these cases, carrier mothers have approximately a 1:10 risk of having a child with Down syndrome; the risk is smaller for carrier fathers. Translocation 21q;21q, which occurs when the extra chromosome 21 is attached to another chromosome 21, is much less common. It is particularly important to determine whether a parent is a carrier of, or a mosaic for, translocation 21q;21q. Each child of a carrier of the translocation will have Down syndrome or monosomy 21. Because monosomy 21 is not typically compatible with life, the risk of having a viable child with Down syndrome is 100%. If the parent is mosaic, that parent has some normal cells and some 45-chromosome cells with 21q;21q, and so the risk of Down syndrome is markedly increased, although these people may also have children with normal chromosomes. Down syndrome mosaicismpresumably results from nondisjunction (when chromosomes fail to pass to separate cells) during cell division in the embryo. People with mosaic Down syndrome have two cell lines, one with the normal 46 chromosomes and another with 47 chromosomes, including an extra chromosome 21. The prognosis for intelligence and risk of medical complications probably depends on the proportion of trisomy 21 cells in each different tissue, including the brain. However, in practice, risk cannot be predicted because it is not feasible to determine the karyotype in every single cell in the body. Some people with mosaic Down syndrome have very subtle clinical signs and may have normal intelligence; however, even people with no detectable mosaicism can have very variable findings. If a parent has germline mosaicism for trisomy 21, an increased risk, above the maternal age-based risk, exists for a second affected child. 1.Antonarakis SE: Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group.N Engl J Med324(13):872-876, 1991. doi: 10.1056/NEJM199103283241302 2.Mutton D, Alberman E, Hook EB: Cytogenetic and epidemiological findings in Down syndrome, England and Wales 1989 to 1993. National Down Syndrome Cytogenetic Register and the Association of Clinical Cytogeneticists.J Med Genet33(5):387-394, 1996. doi: 10.1136/jmg.33.5.387 