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Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart

Rong Mao12, Xiaowen Wang3, Edward L Spitznagel4, Laurence P Frelin5, Jason C Ting5, Huashi Ding3, Jung-whan Kim6, Ingo Ruczinski7, Thomas J Downey3 and Jonathan Pevsner1256*

Author Affiliations

1 Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins School of Medicine, 1830 East Monument Street, Baltimore, MD 21205, USA

2 Department of Neuroscience, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA

3 Partek Incorporated, St Charles, MO 63304, USA

4 Department of Mathematics, Campus Box 1146, Washington University, St Louis, MO 63130, USA

5 Department of Neurology, Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205, USA

6 Pathobiology Graduate Program, Johns Hopkins School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA

7 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA

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Genome Biology 2005, 6:R107  doi:10.1186/gb-2005-6-13-r107

Published: 16 December 2005



Down syndrome, caused by trisomic chromosome 21, is the leading genetic cause of mental retardation. Recent studies demonstrated that dosage-dependent increases in chromosome 21 gene expression occur in trisomy 21. However, it is unclear whether the entire transcriptome is disrupted, or whether there is a more restricted increase in the expression of those genes assigned to chromosome 21. Also, the statistical significance of differentially expressed genes in human Down syndrome tissues has not been reported.


We measured levels of transcripts in human fetal cerebellum and heart tissues using DNA microarrays and demonstrated a dosage-dependent increase in transcription across different tissue/cell types as a result of trisomy 21. Moreover, by having a larger sample size, combining the data from four different tissue and cell types, and using an ANOVA approach, we identified individual genes with significantly altered expression in trisomy 21, some of which showed this dysregulation in a tissue-specific manner. We validated our microarray data by over 5,600 quantitative real-time PCRs on 28 genes assigned to chromosome 21 and other chromosomes. Gene expression values from chromosome 21, but not from other chromosomes, accurately classified trisomy 21 from euploid samples. Our data also indicated functional groups that might be perturbed in trisomy 21.


In Down syndrome, there is a primary transcriptional effect of disruption of chromosome 21 gene expression, without a pervasive secondary effect on the remaining transcriptome. The identification of dysregulated genes and pathways suggests molecular changes that may underlie the Down syndrome phenotypes.