BACKGROUND: Down syndrome, characterized by an extra chromosome 21 is the most 
common genetic cause for congenital malformations and learning disability. It is 
well known that the extra chromosome 21 most often originates from the mother, 
the incidence increases with maternal age, there may be aberrant maternal 
chromosome 21 recombination and there is a higher recurrence in young women. In 
spite of intensive efforts to understand the underlying reason(s) for these 
characteristics, the origin still remains unknown. We hypothesize that maternal 
trisomy 21 ovarian mosaicism might provide the major causative factor.
RESULTS: We used fluorescence in situ hybridization (FISH) with two chromosome 
21-specific probes to determine the copy number of chromosome 21 in ovarian 
cells from eight female foetuses at gestational age 14-22 weeks. All eight 
phenotypically normal female foetuses were found to be mosaics, containing 
ovarian cells with an extra chromosome 21. Trisomy 21 occurred with about the 
same frequency in cells that had entered meiosis as in pre-meiotic and ovarian 
mesenchymal stroma cells.
CONCLUSION: We suggest that most normal female foetuses are trisomy 21 ovarian 
mosaics and the maternal age effect is caused by differential selection of these 
cells during foetal and postnatal development until ovulation. The exceptional 
occurrence of high-grade ovarian mosaicism may explain why some women have a 
child with Down syndrome already at young age as well as the associated 
increased incidence at subsequent conceptions. We also propose that our findings 
may explain the aberrant maternal recombination patterns previously found by 
family linkage analysis.