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On the origin of trisomy 21 Down syndrome

By Maj A. Hultén, Suketu D. Patel, Maira Tankimanova, Magnus Westgren, Nikos Papadogiannakis, Anna Maria Jonsson and Erik Iwarsson

Abstract

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.\ud 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\ud mesenchymal stroma cells.\ud 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\ud 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

Topics: R1
Publisher: BioMed Central Ltd.
Year: 2008
OAI identifier: oai:wrap.warwick.ac.uk:536

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  1. (1976). A: Meiosis of trisomy 21 in the human pachytene oocyte. Behaviour of the supernumerary chromosome, identification of chromomere sequence and numerous sub-bands. Chromosoma doi
  2. (1987). Chromosome 21 behavior during fetal oogenesis in Down's syndrome. Obstet Gynecol
  3. (1973). Cytogenetic aspects of human male meiosis. Advances in Human Genetics doi
  4. (1971). De la Chapelle A: Meiosis and spermatogenesis in G-trisomic males. Humangenetik doi
  5. (1971). De la Chapelle A: Meiosis and spermatogenesis in two postpubertal males with Down's syndrome: 47, XY, G+. Clin Genet doi
  6. (1999). Delhanty JDA: A trisomic germ cell line and precocious chromatid separation causes repeated trisomic conceptions. Hum Genet doi
  7. (1988). E: Multiple recurrence of trisomy 21 Down syndrome. Hum Genet doi
  8. (2008). Faulty spindle checkpoint and cohesion protein activities predispose oocytes to premature chromosome separation and aneuploidy. Environ Mol Mutagen doi
  9. (2006). First years of human chromosomes. The Beginnings of Human Cytogenetics Scion Publishing Ltd; doi
  10. (1970). Further observations of cell selection in vivo in normal-G trisomic mosaics. Nature doi
  11. (1998). Genetic analysis of meiotic recombination in humans by use of sperm typing: reduced recombination within a heterozygous paracentric inversion of chromosome 9q32-q34.3. doi
  12. (2006). Hamamah S: The occurrence of aneuploidy in human: lessons from the cytogenetic studies of human oocytes. doi
  13. (2008). Hassold TJ: Human female meiosis: what makes a good egg go bad? Trends Genet doi
  14. (2002). Hassold TJ: Sex matters in meiosis. Science doi
  15. (2006). Hawley RS: The mechanism of secondary nondisjunction in Drosophila melanogaster females. Genetics doi
  16. (2007). Höög C: Biorientation of achiasmatic chromosomes in meiosis I oocytes contributes to aneuploidy in mice. Nat Genet doi
  17. (2008). Höög C: Disruption of pairing and synapsis of chromosomes causes stage-specific apoptosis of male meiotic cells. Theriogenology doi
  18. (1998). Hultén MA: Combined immunocytogenetic and molecular cytogenetic analysis of meiosis I oocytes from normal human females. Zygote doi
  19. (2002). Hultén MA: Meiotic chromosome pairing in fetal oocytes of trisomy 21 human females. Cytogenet Genome Res doi
  20. (2002). Hultén MA: Patterns of meiotic recombination in human fetal oocytes. doi
  21. (2004). Inter-sex variation in synaptonemal complex lengths largely determine the different recombination rates in male and female germ cells. Cytogenet Genome Res doi
  22. (2004). JL: Cohesin component dynamics during meiotic prophase I in mammalian oocytes. Chromosome Res doi
  23. (2008). Lack of aneuploidy for chromosomes 15, 16, and 18 in placentas from small-for-gestational-age liveborn infants. doi
  24. (2008). Meiosis in oocytes: predisposition to aneuploidy and its increased incidence with age. Hum Reprod Update doi
  25. (1984). Meiotic configurations in female trisomy 21 foetuses. Hum Genet doi
  26. Meiotic studies in humans. In Human Cytogenetics A Practical Approach Edited by: Rooney DE.
  27. (2000). Modeling the maternal-age dependency of reproductive failure and genetic fitness. Evol Dev doi
  28. (1992). Oocyte selection: a new model for the maternal-age dependence of Down syndrome. Hum Genet doi
  29. (2007). Pairing and synapsis in oocytes from female fetuses with euploid and aneuploid chromosome complements. Reproduction doi
  30. (2007). Parenatal mosaicism for trisomy 21. Problems with its detection and an approach to determining its population rate. Genetic Testing doi
  31. (1983). Schwinger E: Down's syndrome in the male. Reproductive pathology and meiotic studies. Hum Genet doi
  32. (2008). SL: New insights into human nondisjunction of chromosome 21 in oocytes. PLoS Genet doi
  33. (2003). Telomereindependent homologue pairing and checkpoint escape of accessory ring chromosomes in male mouse meiosis. doi
  34. (2000). The pachytene checkpoint. Trends Genet doi
  35. (1994). TM: Recurrent Down's syndrome due to maternal ovarian trisomy 21 mosaicism. Arch Gynecol Obstet doi
  36. (1983). Triple chromosome synapsis in oocytes from a human foetus with trisomy 21. Ann Hum Genet doi
  37. (1980). Trisomy 21 mosaicism in two successive generations in a family. doi
  38. (1984). Trisomy in man. Ann Rev Genet doi
  39. (1985). VC: Triploidy and chromosomes. doi
  40. (1990). Wladimiroff JW: Trisomy 21 mosaicism in gonads with unexpectedly high recurrence risks. Am J Med Genet Suppl doi

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