title: On the origin of trisomy 21 Down syndrome.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Warwick Medical School, University of Warwick, UK. maj.hulten@warwick.ac.uk.
authors.forename: Maj A
authors.initials: MA
authors.lastname: Hultén
authors.forename: Suketu D
authors.initials: SD
authors.lastname: Patel
authors.forename: Maira
authors.initials: M
authors.lastname: Tankimanova
authors.forename: Magnus
authors.initials: M
authors.lastname: Westgren
authors.forename: Nikos
authors.initials: N
authors.lastname: Papadogiannakis
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Jonsson
authors.forename: Erik
authors.initials: E
authors.lastname: Iwarsson
references.citation: Clin Genet. 1971;2(1):50-7
references.pmid: 4255785
references.citation: J Med Genet. 1980 Feb;17(1):48-9
references.pmid: 6445007
references.citation: Am J Hum Genet. 1971 Nov;23(6):592-601
references.pmid: 4257130
references.citation: Cytogenet Genome Res. 2004;107(3-4):208-15
references.pmid: 15467366
references.citation: Adv Hum Genet. 1973;4:327-87
references.pmid: 4131530
references.citation: Chromosoma. 1976 Aug 17;57(2):155-63
references.pmid: 60206
references.citation: Nature. 1970 Jul 11;227(5254):163-4
references.pmid: 4246764
references.citation: Chromosome Res. 2004;12(3):197-213
references.pmid: 15125634
references.citation: J Cell Biol. 2003 Sep 1;162(5):795-807
references.pmid: 12952934
references.citation: Cytogenet Genome Res. 2002;96(1-4):45-51
references.pmid: 12438779
references.citation: Science. 2002 Jun 21;296(5576):2181-3
references.pmid: 12077403
references.citation: Am J Hum Genet. 2002 Jun;70(6):1469-79
references.pmid: 11992253
references.citation: Evol Dev. 2000 Jul-Aug;2(4):203-7
references.pmid: 11252563
references.citation: Trends Genet. 2000 Sep;16(9):395-403
references.pmid: 10973068
references.citation: Environ Mol Mutagen. 2008 Oct;49(8):642-58
references.pmid: 18626998
references.citation: PLoS Genet. 2008 Mar;4(3):e1000033
references.pmid: 18369452
references.citation: Hum Reprod Update. 2008 Mar-Apr;14(2):143-58
references.pmid: 18084010
references.citation: Am J Obstet Gynecol. 2008 Feb;198(2):231.e1-7
references.pmid: 17997390
references.citation: Trends Genet. 2008 Feb;24(2):86-93
references.pmid: 18192063
references.citation: Theriogenology. 2008 Feb;69(3):333-9
references.pmid: 17997150
references.citation: Zygote. 1998 Feb;6(1):27-38
references.pmid: 9652069
references.citation: Hum Genet. 1999 Jan;104(1):23-8
references.pmid: 10071188
references.citation: Genet Test. 2007 Fall;11(3):341-4
references.pmid: 17949298
references.citation: Am J Hum Genet. 1998 Jun;62(6):1484-92
references.pmid: 9585591
references.citation: Arch Gynecol Obstet. 1994;255(4):213-6
references.pmid: 7695369
references.citation: Nat Genet. 2007 Aug;39(8):966-8
references.pmid: 17618286
references.citation: Reproduction. 2007 May;133(5):899-907
references.pmid: 17616720
references.citation: Genetics. 2006 Sep;174(1):67-78
references.pmid: 16816415
references.citation: Eur J Med Genet. 2006 Mar-Apr;49(2):103-16
references.pmid: 16530707
references.citation: Hum Genet. 1992 Sep-Oct;90(1-2):1-6
references.pmid: 1427764
references.citation: Am J Med Genet Suppl. 1990;7:186-8
references.pmid: 2149943
references.citation: Am J Obstet Gynecol. 1985 Jan 1;151(1):65-9
references.pmid: 3966508
references.citation: Hum Genet. 1988 Jan;78(1):103-5
references.pmid: 2962924
references.citation: Obstet Gynecol. 1987 Dec;70(6):878-83
references.pmid: 2960924
references.citation: Annu Rev Genet. 1984;18:69-97
references.pmid: 6241455
references.citation: Hum Genet. 1984;66(2-3):176-80
references.pmid: 6232197
references.citation: Ann Hum Genet. 1983 Oct;47(Pt 4):271-6
references.pmid: 6228187
references.citation: Hum Genet. 1983;63(2):132-8
references.pmid: 6220959
references.citation: Humangenetik. 1971;13(1):15-24
references.pmid: 4256013