Down Syndrome

Genetic Forms of DS

All individuals with DS have extra chromosome 21 material. There are 3 genetic mechanisms for trisomy 21. The first and most common, is called non-disjunction, where there is an entire extra chromosome 21 in all cells. A chromosome study (karyotype) of trisomy 21 is shown in Fig. 1.

The second is mosaic DS, where trisomy 21 cells are mixed with a second cell line, usually "normal" (46,XX or 46,XY). Individuals with this form of DS are frequently a bit milder in their presentation, depending on the proportion of normal cells.

The third is a translocation DS, about 3-5% of the total, where part or all of chromosome 21 is translocated to another chromosome, usually 14. Translocation DS does not vary with age. Children with translocation DS are indistinguishable from individuals with the usual form of DS.

Trisomy 21

An extra whole chromosome 21 in all cells examined is found in about 92 per cent of all DS individuals. This is shown in Figure 1. DS is common enough that it may appear that there is an excess cluster or hot spot when several DS children are born in the same area, but this is just chance and statistical variation.

As far as we know, there is no relationship between DS and diet, drugs, economic status, or life style. Some evidence suggests that it is a little more common in families with Alzheimer's disease in one or more older family members.

Non-disjunction results from unequal chromosome division, usually in the mother's egg production. This is the form of DS that increases in incidence with increased maternal age. But DS is so common, it is not rare in young parents.

If a couple has a child with DS, the risk is higher for the next pregnancy (1/100). Obviously, this means that the risk is 99% that the next child will NOT have DS. If the risk is already 1/220 at birth, the risk at age 37, the risk is usually estimated as twice the risk for age. Risks for amniocentesis results are higher because half to three-quarters of DS fetuses die before birth of natural causes.

The risk of DS does not appear increased in siblings of trisomy 21 individuals.

Prenatal testing is always recommended for couples who are worried about a second affected child. But prenatal testing procedures may not be for everyone, since they are expensive and many parents may not want to know or act on the information.

The testing is more than 99 per cent reliable in most genetic centers, only rarely is there a sampling of maternal cells, failure of cells to grow or bacterial or yeast contamination.

Mosaic Trisomy 21

A mosaic DS child has two populations of cells, the trisomy 21 cells, and a second cell line, usually normal. This form is 2-4 % of the DS population. The physical features may be milder in these individuals, particularly if there is a large proportion of normal cells.

It was once thought that the unequal chromosome division of mosaic DS takes place early after fertilization, and is a defect in mitotic cell division. However, CVS studies have shown that a fetus with 47 (XX or XY) + 21 chromosomes can lose an extra 21 chromosome in some cells, providing an alternate mechanism for the mosaic result. Thus, Mosaic DS may also be related to maternal age. This also means that an increased recurrence risk is theoretically possible, and prenatal studies for subsequent pregnancies would be recommended.

Translocation Trisomy 21

In 3 - 4% of DS the extra chromosome 21 is permanently attached to another chromosome causing a translocation. "Translocation" refers to one type of rearrangement of chromosomal material; in DS almost all translocations are Robertsonian translocations, named for Dr. Roberts, an Australian chromosome expert who originally described this type of translocation.

A Robertsonian translocation is formed when one chromosome 21 attaches to another chromosome, forming a single new, chromosome. The recipient chromosome is usually chromosome 14 and the combination of 2 chromosomes is called a fourteen, twenty one translocation, written t(14;21) or t(14q21q). The q refers to the long arm of a chromosome. Here, the long arm of 21 is attached to the long arm of 14.

Karyotypes with a Robertsonian translocation can be balanced or unbalanced. Individuals who have one 21, one 14, and a t(14;21) are balanced: there is no extra or missing chromosomal material. Here there are 45 instead of the usual 46 chromosomes. The one translocation chromosome now carries the original 2 chromosomes. A translocation DS karyotype is shown in Figure 2.

Down syndrome results when there are two chromosomes 21, one 14, and