Gene expression variation increase in trisomy 21 tissues

Chou, Ching Yu; Liu, Liyu; Chen, Chien‐Yu; Tsai, Chao-Ming; Hwa, Hsiao‐Lin; Chang, Li Chien; Lin, Yu-Hsiang; Hsieh, Fon Jou

doi:10.1007/s00335-008-9121-1

Cited by 29 publications

(22 citation statements)

References 32 publications

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“…Chou et al (2008) analyzed variability of expression of euploid genes in four human DS amniocyte samples and six euploid amniocyte samples. They also analyzed three publicly available datasets from fetal brains, adult brains, and fetal hearts.…”

Section: Copy Number Variations (Cnvs) and Hsa21mentioning

confidence: 99%

Molecular genetic analysis of Down syndrome

2009

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Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer's disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex. Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review.

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Section: Copy Number Variations (Cnvs) and Hsa21mentioning

confidence: 99%

Molecular genetic analysis of Down syndrome

2009

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“…To study human fetal development, gene expression studies have largely relied on post-partum or post-mortem tissue samples. Samples from live fetuses have almost exclusively been performed using cultured amniocytes or chorionic villi (Altug-Teber et al 2007; Chung et al 2005; Chou et al 2008). These sample sources are all inherently limited in their ability to reflect in vivo physiology.…”

Section: Introductionmentioning

confidence: 99%

Novel neurodevelopmental information revealed in amniotic fluid supernatant transcripts from fetuses with trisomies 18 and 21

et al. 2012

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Trisomies 18 and 21 are the two most common live born autosomal aneuploidies in humans. While the anatomic abnormalities in affected fetuses are well documented, the dysregulated biological pathways associated with the development of the aneuploid phenotype are less clear. Amniotic fluid (AF) cell-free RNA is a valuable source of biological information obtainable from live fetuses. In this study, we mined gene expression data previously produced by our group from mid-trimester AF supernatant samples. We identified the euploid, trisomy 18 and trisomy 21 AF transcriptomes, and analyzed them with a particular focus on the nervous system. We used multiple bioinformatics resources, including DAVID, Ingenuity Pathway Analysis, and the BioGPS Gene Expression Atlas. Our analyses confirmed that AF supernatant from aneuploid fetuses is enriched for nervous system gene expression and neurological disease pathways. Tissue analysis showed that fetal brain cortex and Cajal–Retzius cells were significantly enriched for genes contained in the AF transcriptomes. We also examined AF transcripts known to be dysregulated in aneuploid fetuses compared with euploid controls and identified several brain-specific transcripts among them. Many of these genes play critical roles in nervous system development. NEUROD2, which was downregulated in trisomy 18, induces neurogenic differentiation. SOX11, downregulated in trisomy 21, is a transcription factor that is essential for pan-neuronal protein expression and axonal growth of sensory neurons. Our results show that whole transcriptome analysis of cell-free RNA in AF from live pregnancies permits discovery of biomarkers of abnormal human neurodevelopment and advances our understanding of the pathophysiology of aneuploidy.

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“…We show that gene expression signature consisting of 9 genes could discriminate Ts21 cases from normal samples (AUC performance estimate reached 0.97 for discrimination of Ts21 samples from controls). We have also demonstrated the high discriminatory performance of the same 9-gene expression signature on data from two previous transcriptome profiling studies, measured either in amniocyte samples or chorionic villus biopsy samples [3,13]. …”

Section: Discussionmentioning

confidence: 69%

Expression Signature as a Biomarker for Prenatal Diagnosis of Trisomy 21

et al. 2013

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A universal biomarker panel with the potential to predict high-risk pregnancies or adverse pregnancy outcome does not exist. Transcriptome analysis is a powerful tool to capture differentially expressed genes (DEG), which can be used as biomarker-diagnostic-predictive tool for various conditions in prenatal setting. In search of biomarker set for predicting high-risk pregnancies, we performed global expression profiling to find DEG in Ts21. 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 expression microarrays. Datasets from Ts21 transcriptomic studies from GEO repository were incorporated. DEG were discovered using linear regression modelling and validated using RT-PCR quantification on an independent sample of 16 cases with Ts21 and 32 controls. The classification performance of Ts21 status based on expression profiling was performed using supervised machine learning algorithm and evaluated using a leave-one-out cross validation approach. Global gene expression profiling has revealed significant expression changes between normal and Ts21 samples, which in combination with data from previously performed Ts21 transcriptomic studies, were used to generate a multi-gene biomarker for Ts21, comprising of 9 gene expression profiles. In addition to biomarker’s high performance in discriminating samples from global expression profiling, we were also able to show its discriminatory performance on a larger sample set 2, validated using RT-PCR experiment (AUC=0.97), while its performance on data from previously published studies reached discriminatory AUC values of 1.00. Our results show that transcriptomic changes might potentially be used to discriminate trisomy of chromosome 21 in the prenatal setting. As expressional alterations reflect both, causal and reactive cellular mechanisms, transcriptomic changes may thus have future potential in the diagnosis of a wide array of heterogeneous diseases that result from genetic disturbances.

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Gene expression variation increase in trisomy 21 tissues

Cited by 29 publications

References 32 publications

Molecular genetic analysis of Down syndrome

Molecular genetic analysis of Down syndrome

Novel neurodevelopmental information revealed in amniotic fluid supernatant transcripts from fetuses with trisomies 18 and 21

Expression Signature as a Biomarker for Prenatal Diagnosis of Trisomy 21

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