Ding Hu, Duan Honglei, Zhu Xiangyu, Liu Wei, Gu Leilei, Li Huijun, Jiang Zihan, Li Jie
Nanjing Drum Tower Clinical College of Xuzhou Medical University, Nanjing, Jiangsu 210008, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Apr 10;40(4):446-451. doi: 10.3760/cma.j.cn511374-20220422-00272.
To explore the genetic etiology and related factors in 1 065 women with spontaneous abortions.
All patients have presented at the Center of Prenatal Diagnosis of Nanjing Drum Tower Hospital from January 2018 to December 2021. Chorionic villi and fetal skin samples were collected, and the genomic DNA was assayed by chromosomal microarray analysis (CMA). For 10 couples with recurrent spontaneous abortions but normal CMA results for abortive tissues, non-in vitro fertilization-embryo transfer (IVF-ET) pregnancies and no previous history of live births and no structural abnormalities of the uterus, peripheral venous blood samples were collected. Genomic DNA was subjected to trio-whole exome sequencing (trio-WES). Candidate variants were verified by Sanger sequencing and bioinformatics analysis. Multifactorial unconditional logistic regression analysis was carried out to analyze the factors that may affect chromosomal abnormality in spontaneous abortions, such as the age of the couple, number of previous spontaneous abortions, IVF-ET pregnancy and history of live birth. The incidence of chromosomal aneuploidies in spontaneous abortions during the first trimester was compared in young or advanced-aged patients by chi-square test for liner trend.
Among the 1 065 spontaneous abortion patients, 570 cases (53.5%) of chromosomal abnormalities were detected in spontaneous abortion tissues, which included 489 cases (45.9%) of chromosomal aneuploidies and 36 cases (3.4%) of pathogenic/likely pathogenic copy number variations (CNVs). Trio-WES results have revealed one homozygote variant and one compound heterozygote variants in two pedigrees, both of which were inherited from the parents. One likely pathogenic variant was detected in the patient from two pedigrees. Multifactorial unconditional Logistic regression analysis suggested that age of patient was an independent risk factor of chromosome abnormalities (OR = 1.122, 95%CI: 1.069-1.177, P < 0.001), the number of previous abortions and IVF-ET pregnancy were independent protective factors for chromosomal abnormalities (OR = 0.791, 0.648; 95%CI: 0.682-0.916, 0.500-0.840; P = 0.002, 0.001), whilst the age of husband and history of live birth were not (P > 0.05). The incidence of aneuploidies in the abortive tissues has decreased with the number of previous spontaneous abortions in young patients (χ² = 18.051, P < 0.001), but was not significantly correlated with the number of previous spontaneous abortions in advanced-aged patients with spontaneous abortions (P > 0.05).
Chromosomal aneuploidy is the main genetic factor for spontaneous abortion, though CNVs and genetic variants may also underlie its genetic etiology. The age of patients, number of previous abortions and IVF-ET pregnancy are closely associated with chromosome abnormalities in abortive tissues.
探讨1065例自然流产女性的遗传病因及相关因素。
所有患者均于2018年1月至2021年12月就诊于南京鼓楼医院产前诊断中心。采集绒毛和胎儿皮肤样本，采用染色体微阵列分析（CMA）检测基因组DNA。对于10对复发性自然流产但流产组织CMA结果正常、非体外受精-胚胎移植（IVF-ET）妊娠、无活产史且子宫无结构异常的夫妇，采集外周静脉血样本。对基因组DNA进行三联体全外显子测序（trio-WES）。通过Sanger测序和生物信息学分析验证候选变异。进行多因素非条件logistic回归分析，分析可能影响自然流产染色体异常的因素，如夫妇年龄、既往自然流产次数、IVF-ET妊娠和活产史。采用线性趋势卡方检验比较年轻或高龄患者孕早期自然流产中染色体非整倍体的发生率。
在1065例自然流产患者中，自然流产组织中检测到570例（53.5%）染色体异常，其中包括489例（45.9%）染色体非整倍体和36例（3.4%）致病性/可能致病性拷贝数变异（CNV）。三联体全外显子测序结果在两个家系中发现1个纯合变异和1个复合杂合变异，均为父母遗传。在两个家系的患者中检测到1个可能致病的变异。多因素非条件logistic回归分析提示，患者年龄是染色体异常的独立危险因素（OR = 1.122，95%CI：1.069 - 1.177，P < 0.001），既往流产次数和IVF-ET妊娠是染色体异常的独立保护因素（OR = 0.791，0.648；95%CI：0.682 - 0.916，0.500 - 0.840；P = 0.002，0.001），而丈夫年龄和活产史则不是（P > 0.05）。年轻患者中，流产组织中非整倍体的发生率随既往自然流产次数的增加而降低（χ² = 18.051，P < 0.001），但在高龄自然流产患者中与既往自然流产次数无显著相关性（P > 0.05）。
染色体非整倍体是自然流产的主要遗传因素，尽管CNV和基因变异也可能是其遗传病因的基础。患者年龄、既往流产次数和IVF-ET妊娠与流产组织中的染色体异常密切相关。
