Abstract
BackgroundDown syndrome (DS), characterized by an extra free chromosome 21 is the most common genetic cause for congenital malformations and learning disability. It is well known that the extra chromosome 21 originates from the mother in more than 90% of cases, the incidence increases with maternal age and there is a high recurrence in young women. In a previous report we have presented data to indicate that maternal trisomy 21 (T21) ovarian mosaicism might provide the major causative factor underlying these patterns of DS inheritance. One important outstanding question concerns the reason why the extra chromosome 21 in DS rarely originates from the father, i.e. in less than 10% of T21 DS cases. We here report data indicating that one reason for this parental sex difference is a very much lower degree of fetal testicular in comparison to ovarian T21 mosaicism.ResultsWe used fluorescence in situ hybridisation (FISH) with two chromosome 21-specific probes to determine the copy number of chromosome 21 in fetal testicular cell nuclei from four male fetuses, following termination of pregnancy for a non-medical/social reason at gestational age 14-19 weeks. The cells studied were selected on the basis of their morphology alone, pending immunological specification of the relevant cell types. We could not detect any indication of testicular T21 mosaicism in any of these four male fetuses, when analysing at least 2000 cells per case (range 2038-3971, total 11.842). This result is highly statistically significant (p < 0.001) in comparison to the average of 0.54% ovarian T21 mosaicism (range 0.20-0.88%) that we identified in eight female fetuses analysing a total of 12.634 cells, as documented in a previous report in this journal.ConclusionBased on these observations we suggest that there is a significant sex difference in degrees of fetal germ line T21 mosaicism. Thus, it would appear that most female fetuses are T21 ovarian mosaics, while in sharp contrast most male fetuses may be either very low grade T21 testicular mosaics or they may be non-mosaics. We further propose that this sex difference in germ line T21 mosaicism may explain the much less frequent paternal origin of T21 DS than maternal. The mechanisms underlying the DS cases, where the extra chromosome 21 does originate from the father, remains unknown and further studies in this respect are required.
Highlights
Down syndrome (DS), characterized by an extra free chromosome 21 is the most common genetic cause for congenital malformations and learning disability
In a previous report we documented an average of 0.54% of trisomy 21 (T21) cell nuclei in fetal ovaries from eight female fetuses [28]
We conclude that there is a substantial sex difference in incidence of fetal germ line T21 mosaicism where most female fetuses may be ovarian T21 mosaics, while males in this study do not show any detectable degree of fetal testicular T21 mosaicism
Summary
Down syndrome (DS), characterized by an extra free chromosome 21 is the most common genetic cause for congenital malformations and learning disability. We here report data indicating that one reason for this parental sex difference is a very much lower degree of fetal testicular in comparison to ovarian T21 mosaicism It is just about 50 years since the genetic background for Down syndrome (DS) was identified [1,2,3] with the most common reason being an extra free chromosome 21, trisomy 21 (T21). A couple of years before the confirmation of the true chromosomal background he identified a biomarker for germ line and somatic chromosomal mosaicism (the typical dermatopglyphics) in parents and sibs [6] In the interim it has become clear, primarily by family linkage studies tracing DNA markers along the length of chromosome 21q between parents and children in DS families that the majority of T21 DS cases inherit the extra chromosome 21 from their mother (more than 90%) while in only a minority (less than 10%) the extra chromosome 21 originates from the father [7,8,9,10,11]. It is generally accepted that a number of other genetic and environmental factors may contribute to the variation in chance of having a child with T21 DS (see e.g. Hunt et al 2008, Jones 2008, Oliver et al 2008, Allen et al 2009, Coppedè 2009, Driscoll et al 2009, Garcia-Cruz et al 2009, Ghosh et al 2009, Hassold and Hunt 2009, Keefe and Liu 2009, Mailhes 2008, Martin 2008, Migliore et al 2009, Vogt et al 2009 [8,9,10,16,17,18,19,20,21,22,23,24,25,26])
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