Gene dosage effects in the heart of fetuses with chromosome 21 trisomy

We compared the gene expression profiles of hearts of human fetuses with and without Hsa21 trisomy by oligonucleotide microarrays. Approximately half of the 15,000 genes examined (87 of the 168 genes on Hsa21) were expressed in the heart at 18–22 weeks of gestation. Hsa21 gene expression was globally upregulated 1.5 fold in trisomic samples. However, not all genes were equally dysregulated and 25 genes were not upregulated. Genes located on other chromosomes were also dysregulated. Functional class scoring and gene set enrichment analyses of 473 genes, differentially expressed between trisomic and non-trisomic hearts, revealed downregulation of mitochondrial genes and upregulation of ECM genes. We also evaluated the expression of Hsa21 miRNAs in fetal hearts by qRT-PCR. We found that miR-99a, let-7c and miR-155 were overexpressed in trisomic hearts, and miR-125b was normoregulated while miR-802 was not expressed. There were no significant differences in gene expression between trisomic fetuses with and without heart defects. We conclude that dosage-dependent upregulation of Hsa21 genes causes dysregulated expression of mitochondrial and ECM genes in the heart of trisomic fetuses.