On the origin of trisomy 21 Down syndrome

Abstract

BackgroundDown 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.ResultsWe 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.ConclusionWe 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.

Non-meiotic chromosome instability in human immature oocytes

“…In fact, a previous work that analysed oocytes from eight euploid fetuses described the presence of aneuploid 21 oogonia, and the authors considered mosaicism in the ovaries as a normal situation in normal female fetuses. 20 Mitotic chromosome segregation errors found in oocytes could have two different explanations. On the one hand, they could have been produced in the first mitotic divisions of the embryo, where the aneuploid cells were later recruited in certain tissues, in this case the ovaries.…”

“…This is the reason why there is an accumulation of these oocytes in the ovarian reserves of older women. 20,33 To shed light on the effect of hormonal stimulation in relation to natural cycles and, later, conclude whether or not the protocols applied favour aneuploid oocyte recruitment and maturation instead of euploid ones, as has been suggested before, 34 more research should be performed.…”

“…8,[13][14][15][16][17][18] It has been postulated that these aneuploid cells could have originated in the early mitotic divisions of the embryo or during mitotic proliferation of the oogonia in embryogenesis. 19,20 Additionally, direct studies in ovaries of euploid fetuses indicate that ovary mosaicism might be a common situation. 20 Structural imbalances in oocytes have also been determined by different cytogenetic approaches.…”

“…19,20 Additionally, direct studies in ovaries of euploid fetuses indicate that ovary mosaicism might be a common situation. 20 Structural imbalances in oocytes have also been determined by different cytogenetic approaches. Using R-banding on fixed MII oocytes, 2.1% of the cells showed structural aberrations, including chromatid and chromosome breaks, acentric fragments and deletions.…”

Errors in Chromosome Segregation During Oogenesis and Early Embryogenesis

“…Most recently it has been suggested that the maternal age effect is a multifactorial trait, and may be influenced by environmental factors ( 8,9 ). Another intriguing possibility it that normal women may be trisomy 21 ovarian mosaics ( [11][12][13] with the potential for oocytes containing three chromosomes 21 accumulating during maturation and when reaching MI undergoing obligatory secondary non-disjunction at AI.…”