Germinal and Somatic Trisomy 21 Mosaicism: How Common is it, What are the Implications for Individual Carriers and How Does it Come About?

Abstract

It is well known that varying degrees of mosaicism for Trisomy 21, primarily a combination of normal and Trisomy 21 cells within individual tissues, may exist in the human population. This involves both Trisomy 21 mosaicism occurring in the germ line and Trisomy 21 mosaicism documented in different somatic tissues, or indeed a combination of both in the same subjects. Information on the incidence of Trisomy 21 mosaicism in different tissue samples from people with clinical features of Down syndrome as well as in the general population is, however, still limited. One of the main reasons for this lack of detailed knowledge is the technological problem of its identification, where in particular low grade/cryptic Trisomy 21 mosaicism, i.e. occurring in less than 3-5% of the respective tissues, can only be ascertained by fluorescence in situ hybridization (FISH) methods on large cell populations from the different tissue samples.In this review we summarize current knowledge in this field with special reference to the question on the likely incidence of germinal and somatic Trisomy 21 mosaicism in the general population and its mechanisms of origin. We also highlight the reproductive and clinical implications of this type of aneuploidy mosaicism for individual carriers. We conclude that the risk of begetting a child with Trisomy 21 Down syndrome most likely is related to the incidence of Trisomy 21 cells in the germ line of any carrier parent. The clinical implications for individual carriers may likewise be dependent on the incidence of Trisomy 21 in the relevant somatic tissues. Remarkably, for example, there are indications that Trisomy 21 mosaicism will predispose carriers to conditions such as childhood leukemia and Alzheimer's Disease but there is on the other hand a possibility that the risk of solid cancers may be substantially reduced.

Keywords: Alzheimer’s Disease.; Trisomy 21; cancer; childhood leukemia; fetus; germ line; mosaicism.

Fig. (1)

Diagram showing percentage incidence of the typical DS dermatoglyphics feature in different groups of subjects aged 15 years or over. The control population incidence is increased more than tenfold in DS cases, and is almost doubled in their mothers, brothers and sisters. The excess is shown by black rectangles. Reproduced from [8].

Fig. (2)

FISH images of fetal ovarian cell nuclei using two chromosome 21-specific probes located near the end of 21q (bottom), one normal disomy 21 nucleus (top) and one T21 cell nucleus (middle) illustrating female T21 germinal mosaicism. Reproduced from [24].

Fig. (3)

FISH images of two AD brain nuclei with disomy 21 (top and bottom) and a nucleus with T21 (middle) revealed by a chromosome 21-specific multicolor probe. Reproduced from [115].

Fig. (4)

Increased proportion of T21 oocytes in the ageing ovary. The OMS hypothesis proposes that the T21 oocytes lag behind during development, resulting in higher proportions of the total oocyte pool over time. The figure illustrates the predicted number of T21 oocytes from birth until menopause (pink line) in comparison to the total (black circles) based on follicle counts (left hand Y axis) by Faddy [142]. The observed incidence (right hand Y axis) of T21 DS births (black squares) is represented by the data of Morris et al. [143]. The offset of the (pink) line showing the predicted number of T21 oocytes is based on the 0.54% mosaicism observed by Hultén et al. [24]. The slope is an approximation generating the expected DS birth rates with increasing maternal age. Note that the figure illustrates the principle of this hypothesis only and the lines drawn are based on rather uncertain estimates. Reproduced from [25].