Analysis of Chromosomal Copy Number in First-Trimester Pregnancy Loss Using Next-Generation Sequencing.

Lei Fan,Xinwei Shi,Wanjiang Zeng,Jianli Wu,Shufang Li,Dongrui Deng,Xing Xin,Suhua Chen,Juan Xiao,Ling Feng,Yuanyuan Wu

doi:10.3389/fgene.2020.545856

Abstract

Embryonic chromosomal abnormality is one of the significant causative factors of early pregnancy loss. Our goal was to evaluate the clinical utility of next-generation sequencing (NGS) technology in identifying chromosomal anomalies associated with first-trimester pregnancy loss. In addition, we attempted to provide fertility guidance to couples anticipating a successful pregnancy. A total of 1,010 miscarriage specimens were collected between March 2016 and January 2019 from women who suffered first-trimester pregnancy loss. Total DNA was isolated from products of conception, and NGS analysis was carried out. We detected a total of 634 cases of chromosomal variants. Among the 634 cases, 462 (72.9%) displayed numerical variants including 383 (60.4%) aneuploidies, 44 (6.9%) polyploidies, and 34 (5.5%) mosaicisms. The other 172 (27.1%) cases showed structural variants including 19 (3.0%) benign copy number variations (CNVs), 52 (8.2%) pathogenic CNVs, and 101 (16%) variants of unknown significance (VOUS) CNVs. When maternal age was ≥ 35 years, the sporadic abortion (SA) group showed an increased frequency of chromosomal variants in comparison with the recurrent miscarriage (RM) group (90/121 vs. 64/104). It was evident that the groups with advanced maternal age had a sharply increased frequency of aneuploidy, whatever the frequency of pregnancy loss (71/121 vs. 155/432, 49/104 vs. 108/349). Our data suggest that NGS could be used for the successful detection of genetic anomalies in pregnancy loss. We recommend that fetal chromosome analysis be offered routinely for all pregnancy losses, regardless of their frequency.

Highlights

Pregnancy loss occurs in nearly 10–15% of all clinically confirmed pregnancies, primarily during the first trimester (Hertz-Picciotto and Samuels, 1988; Rai and Regan, 2006)
We evaluated the feasibility of next-generation sequencing (NGS) in the detection of chromosomal abnormalities in first-trimester pregnancy loss and elucidated the associations, if any, between the chromosomal abnormalities and the pregnancy loss
The remaining 1,006 (99.6%) cases were subjected to copy number variations (CNVs) analysis by NGS

Summary

Introduction

Pregnancy loss occurs in nearly 10–15% of all clinically confirmed pregnancies, primarily during the first trimester (Hertz-Picciotto and Samuels, 1988; Rai and Regan, 2006). 50– 60% of all early pregnancy losses may be attributed to fetal chromosomal abnormalities (Goddijn and Leschot, 2000; van den Berg et al, 2012). Researchers have tried to elucidate the genetic causes of pregnancy loss. G-band karyotyping is a traditional cytogenetic technique employed for the genetic analysis of abortus (Israel et al, 1996; Carp et al, 2001). G-band karyotype analysis cannot detect chromosomal aberrations of less than 5 Mb (Saldarriaga et al, 2015). Failure of culture, contamination from cells of maternal origin, and suboptimal chromosome preparation may lead to erroneous results (Robberecht et al, 2009)

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