Expression Signature as a Biomarker for Prenatal Diagnosis of Trisomy 21

Abstract

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.

Integrated Quantitative Transcriptome Maps of Human Trisomy 21 Tissues and Cells

“…To determine which hypothesis applies to the etiology of DS, a number of investigators have conducted gene-expression studies in mouse models and human tissues or cell lines. Several methods have been used, including microarrays, serial analysis of gene expression (SAGE), Real-Time RT-PCR, RNA-seq or proteomic approaches ( Lockstone et al, 2007 ; Prandini et al, 2007 ; Volk et al, 2013 ; Kong et al, 2014 ; Zhao et al, 2016 ; Liu et al, 2017 ).…”

Transcriptome Profiling Uncovers Potential Common Mechanisms in Fetal Trisomies 18 and 21

“…Studies of the GE profiles in developing fetal or adult tissues in trisomies 21, 18, and other aneuploidies have demonstrated both the dysregulation of specific regions of chromosomes that are present in three copies and the widespread dysregulation of genes in regions of the euploid genome (Altug-Teber et al, 2007 ; FitzPatrick et al, 2002 ; Hui et al, 2012 ; Koide et al, 2011 ; Li et al, 2006 ; Lockstone et al, 2007 ; Mao et al, 2005 ; Slonim et al, 2009 ; Stingele et al, 2012 ; Volk et al, 2013 ). According to these studies, GE alterations cannot be attributed to dosage imbalances alone.…”

Prevalence of very low birthweight, malformation, and low Apgar score among newborns inBrazilaccording to maternal urban or rural residence at birth

“…Adverse pregnancy outcomes such as low birthweight, preterm birth, and congenital birth defects are important risk factors for infant mortality . In turn, these adverse outcomes may be influenced by several conditions such as malnutrition, stress, alcohol intake, smoking, use of illicit drugs, chemical exposure during pregnancy, cesarean delivery, maternal age, prenatal medical visits, genetic factors, obesity, gestational diabetes, eclampsia, and parity …”