Copy number variants and fetal structural abnormalities in stillborn
fetuses: a secondary analysis of the Stillbirth Collaborative Research
Network study
Abstract
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.