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Transcriptomic analysis of cell-free fetal RNA suggests a specific molecular phenotype in trisomy 18

机译:无细胞胎儿RNA的转录组学分析表明三体性18中的特定分子表型

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Trisomy 18 is a common human aneuploidy that is associated with significant perinatal mortality. Unlike the well-characterized “critical region” in trisomy 21 (21q22), there is no corresponding region on chromosome 18 associated with its pathogenesis. The high morbidity and mortality of affected individuals has limited extensive investigations. In order to better understand the molecular mechanisms underlying the congenital anomalies observed in this condition, we investigated the in utero gene expression profile of second trimester fetuses affected with trisomy 18. Total RNA was extracted from cell-free amniotic fluid supernatant from aneuploid fetuses and euploid controls matched for gestational age and hybridized to Affymetrix U133 Plus 2.0 arrays. Individual differentially expressed transcripts were obtained by two-tailed t tests. Over-represented functional pathways among these genes were identified with DAVID and Ingenuity® Pathways Analysis. Results show that three hundred and fifty-two probe sets representing 251 annotated genes were statistically significantly differentially expressed between trisomy 18 and controls. Only 7 genes (2.8% of the annotated total) were located on chromosome 18, including ROCK1, an up-regulated gene involved in valvuloseptal and endocardial cushion formation. Pathway analysis indicated disrupted function in ion transport, MHCII/T cell mediated immunity, DNA repair, G-protein mediated signaling, kinases, and glycosylation. Significant down-regulation of genes involved in adrenal development was identified, which may explain both the abnormal maternal serum estriols and the pre and postnatal growth restriction in trisomy 18. Comparison of this gene set to one previously generated for trisomy 21 fetuses revealed only six overlapping differentially regulated genes. This study contributes novel information regarding functional developmental gene expression differences in fetuses with trisomy 18.
机译:18三体性是人类常见的非整倍性,与围产期死亡率显着相关。与三体性21(21q22)中特征明确的“关键区域”不同,第18号染色体上没有与其发病相关的相应区域。受影响个体的高发病率和高死亡率限制了广泛的研究。为了更好地了解在这种情况下观察到的先天性异常的分子机制,我们研究了受18三体性影响的妊娠中期胎儿的子宫内基因表达谱。从非整倍体胎儿和整倍体的无细胞羊水上清液中提取了总RNA。对照与胎龄匹配,并与Affymetrix U133 Plus 2.0阵列杂交。个体差异表达的转录本通过两尾t检验获得。通过DAVID和Ingenuity ® Pathways Analysis鉴定了这些基因中过度表达的功能途径。结果显示,在18三体体和对照组之间,代表251个注释基因的352个探针组在统计学上有显着差异。只有7个基因(占注释总数的2.8%)位于18号染色体上,其中包括ROCK1,ROCK1是一个上调基因,参与了瓣膜和心内膜的形成。途径分析表明离子运输,MHCII / T细胞介导的免疫,DNA修复,G蛋白介导的信号传导,激酶和糖基化功能受到破坏。确定了与肾上腺发育有关的基因的显着下调,这可能解释了异常的母体血清雌激素以及三体性18的出生前和出生后生长受限。将该基因与先前为21三体性胎儿生成的基因进行比较,发现只有六个重叠差异调节基因。这项研究为有关18三体胎儿的功能发育基因表达差异提供了新的信息。

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