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目的:分析早孕期自然流产的遗传学病因。方法:本研究为回顾性研究。研究对象为2021年1月至2022年12月在青岛大学附属妇女儿童医院因孕6～13周自然流产自愿检测早孕期流产胚胎的患者815例。采用高通量测序技术对流产组织进行检测，利用生物信息学方法分析结果。采用 χ2检验进行统计学分析。 结果:（1）815例研究对象中检出染色体异常525例（64.4%），包括染色体数目异常479例（91.2%，包括非整倍体异常421例和三倍体58例），结构异常（拷贝数变异，copy number variation，CNV）44例（8.4%），单亲二体2例（0.4%）。（2）染色体数目异常以染色体非整倍体最常见（87.9%，421/479），涉及除1号染色体的所有染色体，以16-三体最多（17.5%，84/479），其次为X染色体单体（13.4%，64/479）和22-三体（11.3%，54/479）。27例（5.6%）存在多种染色体异常。在9例常染色体单体中，21号染色体单体7例，18和4号染色体单体各1例。（3）44例结构异常中，发现62个致病性或可能致病性CNV，片段长度为19.58 Mb（1.08～103.81 Mb）。涉及8号染色体的CNV最多，为16个（25.8%，16/62），其次为4号和18号染色体［各6个（9.7%，6/62）］。62个CNV中的10个（16.1%）片段大小≤5 Mb，包括3例微缺失综合征。（4）对低深度全基因组CNV测序（low-depth copy number variation sequencing，CNV-seq）结果未提示常染色体数目异常的胚胎进行荧光定量聚合酶链反应验证，检出2例全染色体组单亲二体，均为父源性单亲二体，为完全性葡萄胎。（5）CNV-seq结果提示胚胎存在CNV的44例中，32例孕妇及其配偶选择进行外周血染色体核型分析，其中一方为染色体平衡易位携带者9例（28.1%）。这9例样本均涉及2条染色体变异，且均位于染色体末端。对于片段大小≤5 Mb的CNV，有2例进行了CytoScan 750K芯片检测，结果与CNV-seq测序结果基本一致。（6）32对进行了外周血染色体核型分析的夫妻中，9对（28.1%）进行了染色体相关区域的荧光原位杂交检测，其中正常6例，异常3例。荧光原位杂交异常区域与染色体核型结果一致。（7）年龄≥35岁的孕妇胚胎染色体异常率，以及胚胎染色体数目异常率明显高于年龄<35岁者［75.8%（182/240）与59.6%（343/575）， χ2=23.37；73.3%（176/240）与53.2%（306/575）， χ2=19.34； P值均<0.001］。2组孕妇的胚胎染色体结构异常率差异无统计学意义。 结论:染色体数目异常是早孕期自然流产的主要原因，在流产年龄≥35岁的孕妇中表现更为明显。CNV-seq可能更适用于早孕期自然流产胚胎的检测。

Objective:To analyze the genetic etiology of spontaneous abortion in the first trimester.Methods:This study was a retrospective analysis. The subjects were 815 pregnant women who voluntarily underwent genetic testing of pregnancy miscarriage embryos due to spontaneous abortion or embryonic development arrest in six to thirteen gestational weeks from January 2021 to December 2022. High-throughput sequencing technology was used to detect the abortion tissue, and the results were analyzed by bioinformatics method. Statistical analysis was conducted using the Chi-square test. Results:(1) Chromosomal abnormalities were detected in 525 out of 815 cases (64.4%), including 479 cases (91.2%) of numerical abnormalities (421 cases of aneuploidy and 58 cases of triploidy), 44 cases (8.4%) of structural abnormalities (copy number variation, CNV), and two cases (0.4%) of uniparental disomy. (2) Among the numerical abnormalities, aneuploidy was the most common (87.9%, 421/479), involving all chromosomes except chromosome 1. Trisomy 16 had the highest frequency (17.5%, 84/479), followed by monosomy X (13.4%, 64/479) and trisomy 22 (11.3%, 54/479). Multiple chromosomal abnormalities were present in 27 cases (5.6%). Among the nine cases of autosomal monosomy, there were seven cases of monosomy 21, and one case each of monosomy 18 and monosomy 4. (3) Among the 44 cases of structural abnormalities, 62 pathogenic or possible pathogenic CNVs were identified, with fragment lengths ranging from 1.08 Mb to 103.81 Mb, averaging 19.58 Mb.Chromosome 8 was the most involved in CNV, with 16 cases (25.8%, 16/62), followed by chromosome 4 and 18 with six cases each (9.7%,6/62).Of the 62 CNVs, ten (16.1%) were ≤5 Mb in size, including three cases of microdeletion syndromes.(4) For embryos without autosomal numerical abnormalities indicated by low-depth copy number variation sequencing (CNV-seq) results, quantitative fluorescence polymerase chain reaction verification was performed, detecting two cases of complete uniparental disomy, both of which were paternal uniparental disomy and identified as complete hydatidiform moles. (5) Among the 44 cases where CNV-seq results indicated the presence of CNV in the embryos, 32 cases opted for peripheral blood karyotype analysis, with nine cases (28.1%) identified as carriers of balanced chromosomal translocations in one of the parents. These nine samples all involved variations in two chromosomes, both located at the chromosome ends. For CNV with fragment sizes≤5 Mb, two cases underwent CytoScan 750K array testing, and the chip results were consistent with the CNV-seq sequencing results. (6) Among the 32 couples who underwent peripheral blood karyotype analysis, nine underwent fluorescence in situ hybridization (FISH) testing for chromosomal regions, with six cases showing normal results and three showing abnormalities. The FISH abnormal regions were consistent with the karyotype results. (7) The rate of chromosomal abnormalities in embryos from pregnant women aged≥35 years, as well as the rate of numerical chromosomal abnormalities, were significantly higher than in those aged <35 years [75.8% (182/240) vs. 59.6% (343/575), χ2=23.37; 73.3% (176/240) vs. 53.2% (306/575), χ2=19.34; both P<0.001]. There was no statistically significant difference in the rate of structural chromosomal abnormalities between the two groups. Conclusion:Abnormal chromosome number is the main cause of spontaneous abortion in the first trimester, which is more obvious in pregnant women with abortion age≥35 years. CNV-seq may be more suitable for the detection of spontaneously aborted embryos in the first trimester.