【摘要】 目的：对于有反复不良孕产史但常规核型分析未见异常者，其潜在的遗传学病因(如隐匿性染色体平衡易位)难以通过传统方法明确。这类复杂结构变异因分辨率限制常被漏诊，成为临床遗传学诊断的难点之一。本研究对有2次异常生育史的夫妇进行遗传学病因诊断及生育指导，旨在为光学基因组图谱(optical genome mapping,OGM)技术在生殖遗传领域的拓展应用提供依据。方法：收集于兰州大学第一医院生殖医学中心就诊、连续2次不良妊娠结局、寻求遗传学病因诊断的1对夫妇的临床资料，包括既往超声检查、染色体核型检查、拷贝数变异测序(copy number variation sequencing,CNV-seq)、荧光原位杂交(fluorescence in situ hybridization,FISH)技术结果。进一步采用OGM技术对夫妇双方外周血样本进行高分辨率全基因组结构变异分析，评估OGM在隐匿性染色体平衡易位，尤其是复杂结构变异诊断中的临床应用价值。结果：该夫妇2次妊娠胎儿的CNV-seq结果分别显示为del(4)(p16.3),3.80Mb及dup(4)(p16.3),3.74 Mb合并del(22)(q13.31～q13.33),4.64 Mb。夫妻双方外周血染色体核型分析均未见明显异常，提示可能为隐匿性染色体平衡易位携带者。OGM检测结果显示，男方携带涉及1、4、22号染色体的隐匿性复杂平衡易位，其断裂点位于与2次胎儿CNV-seq异常片段边界一致的区域内，证实男方为表型正常的复杂平衡易位携带者，2次胎儿的染色体异常均为其亲代减数分裂过程中衍生染色体不平衡分离所致。结论：OGM作为一种高分辨率、超长读长、自动化的新型非测序基因检测技术，在隐匿性平衡易位的检测方面相较于传统细胞遗传学技术更高效。更多还原

【Abstract】 Objective: For couples with recurrent adverse pregnancy outcomes but normal results on conventional karyotype analysis, the underlying genetic causes(such as cryptic chromosomal balanced translocations) are difficult to identify using traditional methods. These complex structure variations are often missed due to resolution limitations, posing a major challenge in clinical genetic diagnosis. This study aims to perform genetic etiological diagnosis and provide reproductive guidance for a couple with two abnormal reproductive histories, and to evaluate the application value of optical genome mapping(OGM) in the field of reproductive genetics.Methods: Clinical data were collected from a couple who attended the Reproductive Medicine Center, First Hospital of Lanzhou University, with two consecutive adverse pregnancy outcomes and seeking genetic diagnosis. Previous results from ultrasonography, chromosomal karyotyping, copy number variation sequencing(CNV-seq), and fluorescence in situ hybridization(FISH) were reviewed. OGM was further performed on peripheral blood samples from both partners to conduct high-resolution, genome-wide structural variation analysis, in order to assess the clinical utility of OGM in detecting cryptic chromosomal balanced translocations, particularly complex structure variations.Results: CNV-seq results from the 2 pregnancies showed del(4)(p16.3), 3.80 Mb, and dup(4)(p16.3), 3.74 Mb combined with del(22)(q13.31-q13.33), 4.64 Mb, respectively. Conventional chromosomal karyotyping of peripheral blood from both parents revealed no obvious abnormalities, suggesting the possibility of a cryptic chromosomal balanced translocation carrier. OGM analysis demonstrated that the male partner carried a cryptic complex balanced translocation involving chromosomes 1, 4, and 22. The breakpoints were located in regions consistent with the boundaries of the abnormal CNV segments identified in both fetuses. These findings confirmed that the male partner was a phenotypically normal carrier of a complex balanced translocation, and that the chromosomal abnormalities in both fetuses resulted from unbalanced segregation of derivative chromosomes during parental meiosis.Conclusion: As a novel non-sequencing-based genomic technology characterized by high resolution, ultra-long read length, and automation, OGM is more efficient than traditional cytogenetic techniques in detecting cryptic balanced translocations.更多还原