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

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Abstract

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.

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Acknowledgments

The project described was supported by Award Number R01 HD 042053-07 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (to DWB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the National Institutes of Health. The work was also supported by National Institutes of Health grant R01 HD 058880-01 (to DKS). The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Division of Genetics, Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center, 800 Washington Street, Box 394, Boston, MA, 02111, USA

    Keiko Koide, Kirby L. Johnson, Janet M. Cowan & Diana W. Bianchi

  2. Department of Computer Science, Tufts University School of Engineering, Medford, MA, 02155, USA

    Donna K. Slonim

  3. Department of Pathology, Women and Infants’ Hospital, Providence, RI, 02905, USA

    Umadevi Tantravahi

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  1. Keiko Koide
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  2. Donna K. Slonim
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  4. Umadevi Tantravahi
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  5. Janet M. Cowan
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  6. Diana W. Bianchi
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Correspondence to Diana W. Bianchi.

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Koide, K., Slonim, D.K., Johnson, K.L. et al. Transcriptomic analysis of cell-free fetal RNA suggests a specific molecular phenotype in trisomy 18. Hum Genet 129, 295–305 (2011). https://doi.org/10.1007/s00439-010-0923-3

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