Genetics of Down Syndrome (Trisomy 21)

Trisomy 21 (Down Syndrome) was first reported by Down in 1866 (Down, 1866). It is one of the most common chromosomal disorders, occuring once in every 650 to 1,000 live births (Hook, 1982). It appears to occur with approximately equal frequency across ethnicities (Christianson, 1996). Trisomy 21 infants occur less frequently among live births to mothers at age 20 (1/1600) than at age 35 (1/370), but most infants are born to younger mothers. Therefore, most (75-80%) Down syndrome children are born to young women. Trisomy 21 is characterized by distinct phenotypic features, such as a broad face, narrow, upslanting eyes, and a large protruding tongue. Other visible characteristics include short stature, small ears with a folded helix, and broad hands with a Simian crease. Down syndrome leads to retardation and often disorders of the heart (particularly atrioventricular) and gastrointestinal tract (such as misformed intestines or anus) as well.

Down syndrome also correlates positively with the development of Alzheimer disease (or at least Alzheimer symptoms) much earlier than for the population on average (Wisniewski et al., 1985).

Also, leukemia has a significantly higher incidence rate (10 to 20 times higher, but still less than 3%) for those with Trisomy 21 than for the rest of the population (Zipursky et al., 1987).

Inheritance of Down syndrome is still not completely understood, but it has been well established that the risk of having a child with trisomy 21 increases with maternal age, particularly after 35. For example, the risk of having a liveborn with Down syndrome at maternal age 30 is 1 in 1,000 and at maternal age 40 is 9 in 1,000 (Hook et al., 1983).

Down syndrome is generally (95%) caused by 3 free copies of the 21st chromosome. The remaining 5% results from translocation of an additional copy to another chromosome, from tetrasomy of the 21st chromosome, or from duplicated regions within the chromosome. Molecular techniques have given considerable insight into the origin of the additional genetic material that leads to Down syndrome. The availability of highly informative DNA markers has allowed the parental origin of the extra chromosome 21 and the meiotic/mitotic origin to be determined (Antonarakis, 1993). Most division errors in meiosis that lead to trisomy 21 are maternal, less than 5% are paternal. This is believed to be a direct consequence of the "suspended" division that female gametes undergo (as opposed to continual spermatogenesis over most of the life time of an individual). Most errors (about 78%) in maternal meiosis occur in meiosis I. In the cases where there is paternal nondisjunction, most of the errors occur in meiosis II with no parental age effect. In about 5% of Down syndrome individuals the additional chromosome 21 material appears due to a division error in the zygote. The actual molecular mechanism that leads to these errors is still poorly understood.

In addition to determining in which individual the mutation first occurred, DNA markers have allowed the meiotic/mitotic origin to be determined. Roughly 400 families have been studied (Antonarakis et al., 1991, 1992 [a][b]; Antonarakis, 1993; Sherman et al., 1991, 1992[a] & [b]). Most defects in maternal meiosis occur in meiosis I and the prevalence of this type of error in particular increases sharply at about 35 years of age. Meiosis I accounts for approximately 80% of maternal meiotic errors. Combining this with the total number of maternal trisomy 21 errors yields reveals that roughly 70% of all instances of free trisomy 21 are maternal meiosis I errors. The second most common error is maternal meiosis II. These errors constitute about 20% of maternal errors and close to 20% of all triplicate 21 errors. Maternal age also correlates with meiosis II errors. Paternal nondisjunctions are very rare and tend to occur in meiosis II. The ages for both parents is uncorrelated with frequency of incidence. In the 5% of Down syndrome individuals in which the error occurs post-fertilization, the additional chromosome 21 material results from a mitotic error. Both parents ages again appear irrelevant.

Mapping of the 21^st chromosome in relation to Down syndrome has focused on determining the critical region, that if present in triplicate or greater copies, results in the phenotype characteristic of Down syndrome. To this end, DNA has been examined from individuals who have partial duplication of chromosome 21, both with and without the Down syndrome phenotype (Rahmani et al., 1989; McCormick et al., 1989; Korenberg et al., 1990; Delabar et al., 1993; Korenberg, 1993).

To date, the results of these analyses has been inconclusive. However approximately 5 Mb between loci D21S58 and D21S42 has been correlated with mental retardation and with facial features, such as the protruding tongue and upslanting eyes. Additional phenotypic characteristics may map outside the minimum critical region. Material from other rare patients who have features of Down syndrome but no visible chromosomal abnormality may help to narrow down the critical region. In several such studies, however, no triplicate region has been identified (McCormick et al., 1989; Delabar et al., 1993). These patients may be suffering from an undiagnosed disorder that shares phenotypic characteristics with Down syndrome.

Other studies (Daumer-Hass, 1994), have found contradictory evidence as to the location of various phenotypic sites. Some evidence has been presented that Down syndrome facial characteristics are located in the D21S55 (band 21q22) while a few individuals have been found to have the common facial characteristics of Down syndrome without this area. In particular, one individual with very common expression of Down syndrome was found to be genotypically normal from D21S55 and D21S123. The fact that this individual exemplified the symptoms of Down syndrome without the entire 21q22 region weakens the idea some have advance that this band is the Down syndrome Critical Region (DCR). It appears more likely, that instead of a single critical region, Down syndrome develops as a complex reaction between several genes (Duamer-Haas, 1994). Korenberg et al. (1994) constructed a map of 25 different sites that included appear likely to contain the genes responsible for Down syndrome using in situ fluorescence hybridization and Southern blotting. This study provides additional evidence for a significant contribution of genes outside the D21S55 region to the Down syndrome phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and mental retardation. The results strongly suggest that DS is a contiguous gene syndrome and underscore the unlikeliness of an exclusive DCR.

There is presently no treatment for Down's syndrome. Gene therapy appears to be a promising alternative, but is still years away from widespread application. At present, prenatal testing remains the best option, particularly for older mothers (because of their higher risk).

 The maternal serum alpha feto-protein (MSAFP) is measured by a blood test in the pregnant woman at 15 to 18 weeks of gestation. AFP is made in the fetal liver, and some escapes into the maternal circulation. It is widely used as a screening test for a Down syndrome fetus. MSAFP and at least 1 other screening test (see below) are recommended for all pregnancies not having amniocentesis by the American College of Obstetrics, and the American College of Medical Genetics. MSAFP testing is based on the fact that Down syndrome fetuses tend to be a little smaller on average, have smaller placentas, and thus secrete less MSAFP and other materials, which are determined in the serum of the pregnant woman. Factors that affect this test include gestational age, maternal weight, diabetes and ethnicity.

MSAFP screening is not a definitive test. If the MSAFP test is low it suggests the risk of a Down syndrome fetus equal to the risk of a woman age 35, and prenatal testing/chromosome studies are suggested if the parents want this information. If MSAFP alone is tested, 20 per cent of Down syndrome fetuses will test low. Additional biochemical tests can be used to make more accurate determinations. If MSAFP and human chorionic gonadotrophin (HCG) are determined together, 50 - 60% of Down syndrome fetuses will be identified. If MSAFP, HCG and estradiol are all tested, 60 - 70% of Down syndrome fetuses will be identified. It is important to note that positive screening tests only suggest that the risk of Down syndrome is increased. In those cases, more definitive tests can be used.

More invasive prenatal testing can be done at 10 to 11 weeks by chorion villus biopsy (CVS). This test is second only to Amniocentesis (see below) in commonness. The CVS test is done earlier and is usually more rapid than amniocentesis. There is a small chance of maternal cell contamination preventing accurate diagnosis, and the risk of miscarriage increases slightly after the procedure.

Amniocentesis, a sampling of the amniotic fluid surrounding the fetus, is a the most common form of prenatal testing. It is routinely performed at 14 to 16 weeks of age. Amniocentesis testing for chromosome disorders is very (~99%) reliable for chromosome number, and there is a very slight risk of miscarriage associated with the procedure.

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