Among full autosomal trisomies, only trisomies of chromosome 21 (Down syndrome), 18 (Edwards syndrome) and 13 (Patau syndrome) are compatible with postnatal survival. But the mechanisms, how a supernumerary chromosome disrupts the normal development and causes specific phenotypes, are still not fully explained. As an alternative to gene dosage effect due to the trisomic chromosome a genome-wide transcriptional dysregulation has been postulated. The aim of this study was to define the transcriptional changes in trisomy 13, 18, and 21 during early fetal development in order to obtain more insights into the molecular etiopathology of aneuploidy. Using oligonucleotide microarrays, we analyzed whole genome expression profiles in cultured amniocytes (AC) and chorionic villus cells (CV) from pregnancies with a normal karyotype and with trisomies of human chromosomes 13, 18 and 21. We observed a low to moderate up-regulation for a subset of genes of the trisomic chromosomes. Transcriptional levels of most of the genes on the supernumerary chromosome appeared similar to the respective chromosomal pair in normal karyotypes. A subset of chromosome 21 genes including the DSCR1 gene involved in fetal heart development was consistently up-regulated in different prenatal tissues (AC, CV) of trisomy 21 fetuses whereas only minor changes were found for genes of all other chromosomes. In contrast, in trisomy 18 vigorous downstream transcriptional changes were found. Global transcriptome analysis for autosomal trisomies 13, 18, and 21 supported a combination of the two major hypotheses.

Aït Yahya-Graison E, Aubert J, Dauphinot L, Rivals I, Prieur M, et al: Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. Am J Hum Genet 81:475–491 (2007).
Amano K, Sago H, UchikawaC, Suzuki T, Kotliarova SE, et al: Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome. Hum Mol Genet 13:1333–1340 (2004).
Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S: Chromosome 21 and Down syndrome: from genomics to pathophysiology. Nat Rev Genet 5:725–738 (2004).
Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, et al: NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441:595–600 (2006).
Bamforth SD, Braganca J, Eloranta JJ, Murdoch JN, Marques FI, et al: Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nat Genet 29:469–474 (2001).
Barlow GM, Chen XN, Shi ZY, Lyons GE, Kurnit DM, et al: Down syndrome congenital heart disease: a narrowed region and a candidate gene. Genet Med 3:91–101 (2001).
Carothers AD: A cytogenetic register of trisomies in Scotland: results of the first 2 years (1989, 1990). Clin Genet 46:405–409 (1994).
Dauphinot L, Lyle R, Rivals I, Dang MT, Moldrich RX, et al: The cerebellar transcriptome during postnatal development of the Ts1Cje mouse, a segmental trisomy model for Down syndrome. Hum Mol Genet 14:373–384 (2005).
Dermitzakis ET, Reymond A, Lyle R, Scamuffa N, Ucla C, et al: Numerous potentially functional but non-genic conserved sequences on human chromosome 21. Nature 420:578–582 (2002).
Epstein CJ: Down syndrom (Trisomy 21), in Scriver CR, Beaudet AL, Sly WS (eds): The Metabolic and Molecular Bases of Inherited Disease, pp 1223–1263 (McGraw Hill Medical Publishing Division, New York 2001).
FitzPatrick DR, Ramsay J, McGill NI, Shade M, Carothers AD, Hastie ND: Transcriptome analysis of human autosomal trisomy. Hum Mol Genet 11:3249–3256 (2002).
Fuentes JJ, Genesca L, Kingsbury TJ, Cunningham KW, Perez-Riba M, et al: DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet 9:1681–1690 (2000).
Goossens K, Van Poucke M, Van Soom A, Vandesompele J, Van Zeveren A, Peelman LJ: Selection of reference genes for quantitative real-time PCR in bovine preimplantation embryos. BMC Dev Biol 5:27 (2005).
Hassold T, Hunt P: To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2:280–291 (2001).
Hellemans J, Mortier G, De Paepe A, Speleman F, Vandesompele J: qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol 8:R19 (2007).
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, et al: Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4:249–264 (2003).
Kahlem P, Sultan M, Herwig R, Steinfath M, Balzereit D, et al: Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of Down syndrome. Genome Res 14:1258–1267 (2004).
Korenberg JR, Kawashima H, Pulst SM, Ikeuchi T, Ogasawara N, et al: Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. Am J Hum Genet 47:236–246 (1990).
Lam WWK, Kirk J, Manning N, Reardon W, Kelley RI, FitzPatrick D: Decreased cholesterol synthesis as a possible aetiological factor in malformations of trisomy 18. Eur J Med Genet 46:195–199 (2006).
Li CM, Guo M, Salas M, Schupf N, Silverman W, et al: Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21. BMC Med Genet7:24 (2006).
Mao R, Zielke CL, Zielke HR, Pevsner J: Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. Genomics 81:457–467 (2003).
Mao R, Wang X, Spitznagel EL Jr, Frelin LP, Ting JC, et al: Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart. Genome Biol 6:R107 (2005).
Minami T, Horiuchi K, Miura M, Abid MR, Takabe W, et al: Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J Biol Chem 279:50537–50554 (2004).
Olson LE, Richtsmeier JT, Leszl J, Reeves RH: A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306:687–690 (2004).
Rasmussen R: Quantification on the LightCycler, in Meurer S, Wittwe C, Nakagawara K (eds): Rapid Cycle Real-time PCR, Methods and Applications, pp 21–34 (Springer Press, Heidelberg 2001).
Saran NG, Pletcher MT, Natale JE, Cheng Y, Reeves RH: Global disruption of the cerebellar transcriptome in a Down syndrome mouse model. Hum Mol Genet 12:2013–2019 (2003).
Shapiro BL: Down syndrome – a disruption of homeostasis. Am J Med Genet 14:241–269 (1983).
Sperling S, Grimm CH, Dunkel I, Mebus S, Sperling HP, et al: Identification and functional analysis of CITED2 mutations in patients with congenital heart defects. Hum Mutat 26:575–582 (2005).
Tang Y, Schapiro MB, Franz DN, Patterson BJ, Hickey FJ, et al: Blood expression profiles for tuberous sclerosis complex 2, neurofibromatosis type 1, and Down syndrome. Ann Neurol 56:808–814 (2004).
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, et al: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3: RESEARCH0034 (2002).
Withington SL, Scott AN, Saunders DN, Lopes Floro K, Preis JI, et al: Loss of Cited2 affects trophoblast formation and vascularization of the mouse placenta. Dev Biol 294:67–82 (2006).
Yamakawa K, Huo YK, Haendel MA, Hubert R, Chen XN, et al: DSCAM: a novel member of the immunglobulin superfamily maps in a Down syndrome region and is involved in the development of the nervous system. Hum Mol Genet7:227–237 (1998).
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