妊娠丢失的遗传决定因素：机制、诊断进展及临床意义

摘要(中文译文)

妊娠丢失影响高达15%的临床确认妊娠，构成重大的临床与情感负担。虽然染色体异常占早期流产的大多数，但许多既往不明原因的病例涉及单基因、线粒体、表观遗传、免疫遗传及父源因素。基因组技术的进步提高了对散发性和复发性妊娠丢失中致病性变异的检出能力。旨在综合当前关于妊娠丢失遗传决定因素的证据，涵盖染色体、单基因、线粒体、表观遗传、免疫及血栓形成倾向相关通路，并评估基因组诊断如何指导临床管理与生殖咨询。本叙述性综述整合了关于染色体异常、拷贝数变异、母源效应基因、父源遗传贡献、线粒体功能障碍、表观遗传失调、免疫介导机制及遗传性血栓形成倾向的研究数据。来自下一代测序、染色体微阵列、全外显子组测序及胚胎植入前遗传学检测的证据突出了诊断检出率与临床相关性。染色体异常，包括非整倍体及致病性拷贝数变异，仍是早期妊娠丢失的主要原因。母源效应基因突变、纤毛发生与形态发生缺陷、线粒体变异、印记紊乱及父源因素（如精子DNA碎片化）亦参与植入失败、胚胎停育及复发性丢失。免疫遗传及血栓形成倾向相关变异影响胎盘发育及晚期结局。基因组平台（CMA、WES、NGS、PGT）提高了诊断检出率并改善咨询，尤其对于复发性丢失。妊娠丢失源于染色体异常之外的一系列遗传机制。整合基因组、免疫及环境评估可提高诊断精确性，支持风险分层，并指导针对性管理。现代遗传学检测应作为妊娠丢失综合评估的一部分。妊娠丢失的遗传因素涵盖染色体异常、单基因疾病、线粒体变异、表观遗传紊乱、免疫失调及血栓形成倾向。基因组检测的进步提高了诊断精确性，并支持对受累患者进行个体化生殖咨询。

Abstract

Pregnancy loss affects up to 15% of clinically recognized pregnancies, posing a major clinical and emotional burden. While chromosomal abnormalities account for most early miscarriages, many previously unexplained cases involve monogenic, mitochondrial, epigenetic, immunogenetic, and paternal factors. Advances in genomic technologies have improved detection of pathogenic variants in both sporadic and recurrent pregnancy loss. To synthesize current evidence on genetic determinants of pregnancy loss across chromosomal, monogenic, mitochondrial, epigenetic, immunologic, and thrombophilia-related pathways, and evaluate how genomic diagnostics inform management and reproductive counseling. This narrative review integrates data from studies on chromosomal abnormalities, copy-number variants, maternal-effect genes, paternal genetic contributions, mitochondrial dysfunction, epigenetic dysregulation, immune-mediated mechanisms, and inherited thrombophilias. Evidence from next-generation sequencing, chromosomal microarray, whole-exome sequencing, and preimplantation genetic testing highlights diagnostic yield and clinical relevance. Chromosomal abnormalities, including aneuploidy and pathogenic copy-number variants, remain the predominant cause of early pregnancy loss. Mutations in maternal-effect genes, ciliogenesis and morphogenesis defects, mitochondrial variants, imprinting disturbances, and paternal factors, such as sperm DNA fragmentation, also contribute to implantation failure, embryonic arrest, and recurrent loss. Immunogenetic and thrombophilia-associated variants affect placental development and late outcomes. Genomic platforms (CMA, WES, NGS, PGT) increase diagnostic detection and improve counseling, especially for recurrent loss. Pregnancy loss arises from a spectrum of genetic mechanisms beyond chromosomal abnormalities. Integrating genomic, immunologic, and environmental assessment improves diagnostic precision, supports risk stratification, and informs targeted management. Modern genetic testing should be part of comprehensive evaluation for pregnancy loss. Genetic contributors to pregnancy loss span chromosomal abnormalities, single-gene disorders, mitochondrial variants, epigenetic disturbances, immune dysregulation, and thrombophilia. Advances in genomic testing improve diagnostic precision and support individualized reproductive counseling for affected patients.

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