Unknown,Transcriptomics,Genomics,Proteomics

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Expression signature as a biomarker for prenatal diagnosis of trisomy 21

ABSTRACT: To date, a universal biomarker panel with a potential to predict high-risk pregnancies or adverse pregnancy outcome does not exist. Transcriptomic approach, a measure of gene expression levels across the genome, is a powerful tool to capture differentially expressed genes (DEG) in various conditions, including human trisomy of chromosome 21 (Ts21). DEG can be used to design a biomarker set as a diagnostic-predictive tool for various conditions of heterogeneous aetiology in a prenatal setting. In the search of novel biomarker set to predict high-risk pregnancies, we performed global expression profiling to find DEG in Ts21 used as a model. Subsequently we performed targeted validation and diagnostic performance evaluation on a larger group of case and control samples. Initially, transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using Agilent 4x44K expression microarrays. DEG were discovered using linear regression modelling implemented in limma package. Datasets from Ts21 transcriptomic studies available at GEO repository were incorporated to select our preliminary top DEG. Subsequently, selected top DEG were validated using RT-PCR quantification on independent sample of 16 cases with Ts21 and 32 controls, as well as new datasets from previously performed expression studies in Ts21. The classification was performed using support vector machine classification kernel and evaluated using leave-one-out cross validation approach. Transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using Agilent 4x44K expression microarrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Ales Maver

PROVIDER: E-GEOD-48051 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Among full autosomal trisomies, only trisomies of chromosome 21 (Down syndrome, DS), 18 (Edward syndrome, ES) and 13 (Patau syndrome, PS) 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 effects 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 define whether (1) overexpression of genes of the trisomic chromosome contributes solely to the phenotype, if (2) all genes of the trisomic chromosome are upregulated similarly and whether the ratio of gene expression is in agreement with the gene dosis, (3) whether the different trisomies behave similarly in the characteristics of transcriptional dysregulation, and (4) whether transcriptional pattern can be potentially used in prenatal diagnosis. Methods: Using oligonucleotide microarrays (Affymetrix, U133 Plus 2.0), we analyzed whole genome expression profiles representing 54.000 probe sets in cultured amniocytes (AC) and chorion villus cells (CV) from pregnancies with a normal karyotype and with trisomies of human chromosomes 21, 18 and 13. Findings: We observed a low to moderate up-regulation for a subset of genes of the trisomic chromosomes. Transcriptional level of approximately 12-13 % of the supernumerary chromosome appeared similar to the respective chromosome pair in normal karyotypes. Expression values as well as the expression patterns of genes from the trisomic chromosome can distinguish the respective trisomic samples from euploid controls. A subset of chromosome 21-genes including the DSCR1-gene involved in fetal heart development was consistently up-regulated in different tissues (AC, CV) of trisomy 21 fetuses whereas only minor changes were found for genes of all other chromosomes. In contrast, in trisomy 13 and trisomy 18 vigorous downstream transcriptional changes were found. Interpretation: Global transcriptome analysis for autosomal trisomies 13, 18, and 21 supported a combination of the two major hypotheses. As several transcriptional pathways are altered, complex regulatory mechanisms are involved in the pathogenesis of autosomal trisomies. A genome-wide transcriptional dysregulation was predominantly observed in trisomies 13 and 18, whereas a more to chromosome 21 restricted expression alteration was found in trisomy 21. Experiment Overall Design: The study included the following samples: Three samples with normal chromosomes in Amniocytes (AC) and chorion villus cells (CV) each, three samples with trisomy 13 in AC, three samples with trisomy 18 in CV, and three samples with trisomy 21 in AC and CV each.

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Expression signature as a biomarker for prenatal diagnosis of trisomy 21

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