Systematic analysis of copy‐number variations associated with early pregnancy loss

ABSTRACT Objectives Embryonic numerical and structural chromosomal abnormalities are the most common cause of early pregnancy loss. However, the role of submicroscopic copy‐number variations (CNVs) in early pregnancy loss is unclear, and little is known about the critical regions and candidate genes for miscarriage, because of the large size of structural chromosomal abnormalities. The aim of this study was to identify potential miscarriage‐associated submicroscopic CNVs and critical regions of large CNVs as well as candidate genes for miscarriage. Methods Over a 5‐year period, 5180 fresh miscarriage specimens were investigated using quantitative fluorescent polymerase chain reaction/CNV sequencing or chromosomal microarray analysis. Statistically significant submicroscopic CNVs were identified by comparing the frequency of recurrent submicroscopic CNVs between cases and a published control cohort. Furthermore, genes within critical regions of miscarriage‐associated CNVs were prioritized by integrating the Residual Variation Intolerance Score and the human gene expression dataset for identification of potential miscarriage candidate genes. Results Results without significant maternal‐cell contamination were obtained in 5003 of the 5180 (96.6%) cases. Clinically significant chromosomal abnormalities were identified in 59.1% (2955/5003) of these cases. Three recurrent submicroscopic CNVs (microdeletions in 22q11.21, 2q37.3 and 9p24.3p24.2) were significantly more frequent in miscarriage cases, and were considered to be associated with miscarriage. Moreover, 44 critical regions of large CNVs were observed, including 14 deletions and 30 duplications. There were 309 genes identified as potential miscarriage candidate genes through gene‐prioritization analysis. Conclusions We identified potential miscarriage candidate CNVs and genes. These data demonstrate the importance of CNVs in the etiology of miscarriage and highlight the importance of ongoing analysis of CNVs in the study of miscarriage. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.