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Copy number variants and fetal structural abnormalities in stillborn fetuses: a secondary analysis of the Stillbirth Collaborative Research Network study
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  • Tsegaselassie Workalemahu,
  • Susan Dalton,
  • Shannon Son,
  • Amanda Allshouse,
  • Andrew Carey,
  • Jessica Page,
  • Nathan Blue,
  • Vanessa Thorsten,
  • Robert Goldenberg,
  • Halit Pinar,
  • Uma Reddy,
  • Robert Silver (USA)
Tsegaselassie Workalemahu
University of Utah Health

Corresponding Author:[email protected]

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Susan Dalton
University of Utah Health
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Shannon Son
University of Utah Health
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Amanda Allshouse
University of Colorado
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Andrew Carey
University of Utah Health
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Jessica Page
Intermountain Medical Center
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Nathan Blue
University of Utah Health
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Vanessa Thorsten
RTI International
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Robert Goldenberg
Columbia University
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Halit Pinar
Brown University Warren Alpert Medical School
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Uma Reddy
Yale University School of Medicine
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Robert Silver (USA)
University of Utah
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Objective To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses. Design A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study. Setting Multicenter, 59 hospitals in 5 geographic regions in the USA. Population 384 stillbirth cases of the SCRN study (2006-2008). Methods FSMs were grouped by anatomic system and specific malformation type (e.g., central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500kb. CNVs were classified into two groups: normal, defined as no CNVs>500kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. Main outcome measures The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without FSMs using the Wald Chi-squared test. Results The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs compared with those with normal CNVs (46.7% vs. 19.6%; p-value<0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by craniofacial and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g., CHD1L) and a duplication of 21q22.13 involving 4 genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively. Conclusion Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counseling and care surrounding pregnancies affected by FSMs at risk for stillbirth.
11 Nov 2022Submitted to BJOG: An International Journal of Obstetrics and Gynaecology
17 Nov 2022Submission Checks Completed
17 Nov 2022Assigned to Editor
17 Nov 2022Review(s) Completed, Editorial Evaluation Pending
21 Nov 2022Reviewer(s) Assigned
03 Mar 2023Editorial Decision: Revise Major
07 May 20231st Revision Received
09 May 2023Submission Checks Completed
09 May 2023Assigned to Editor
09 May 2023Review(s) Completed, Editorial Evaluation Pending
15 May 2023Editorial Decision: Accept