表型正常的夫妇反复妊娠21-三体胎儿的遗传学分析及文献复习

Phenotypically normal couples with recurrent pregnancies of trisomy 21 fetus: genetic analysis and literature review

目的探讨一对表型正常夫妇3次妊娠21-三体胎儿的遗传学病因。方法回顾性分析2023年12月由外院转诊至山东省妇幼保健院的表型正常但曾有3次妊娠21-三体胎儿的夫妇,联合应用荧光定量聚合酶链反应(quantitative fluorescence polymerase chain reaction,QF-PCR)、染色体核型分析、染色体微阵列分析(chromosome microarray analysis,CMA)和荧光原位杂交(fluorescencein situ hybridization,FISH)等技术进行遗传学分析。以"反复妊娠""连续妊娠""两次妊娠""21-三体"唐氏综合征"为检索词,在中国知网、万方数据库、中华医学期刊全文数据库和维普中文期刊中检索文献报道;以"recurrence or recurrent""trisomy 21 syndrome""Down syndrome"为检索词,在PubMed、Embase和Web of Science数据库中检索文献报道,检索时间截至2023年12月31日,分析及总结反复妊娠21-三体病例的遗传学病因。结果(1)本院病例:此次妊娠羊水细胞QF-PCR、染色体核型分析和CMA结果均提示胎儿为21-三体,孕妇口腔黏膜细胞、蜕膜组织和尿沉渣细胞FISH检测提示孕妇为21-三体嵌合体。同时,QF-PCR对21号染色体短串联重复序列(short tandem repeat,STR)位点检测推测孕妇可能存在生殖腺嵌合现象,胎儿多余的一条21号染色体来源于生殖腺嵌合的21-三体细胞。(2)文献复习:共检索到有详细记录反复妊娠21-三体病史信息及夫妇双方相关检测结果的13例病例报道,加上本例共14例,其中有2次和3次21-三体妊娠史各7例;2例每次妊娠均为易位型21-三体。14例中,5例仅进行夫妇外周血样本检测,结果未见异常,其余9例还分别进行皮肤成纤维细胞(6例)、卵巢组织细胞(2例)、口腔黏膜细胞(2例)、精液(2例)、尿沉渣细胞(1例)检测;6例提示亲本之一为嵌合型21-三体,5例为女方嵌合,1例为男方嵌合,其中仅2例发现外周血样本中存在嵌合型21-三体细胞,且嵌合比例低于其他同时检测的样本。5例通过检测21号染色体STR位点发现多余的一条21号染色体来源于母亲。结论亲代嵌合体是反复妊娠21-三体的重要病因,对皮肤、口腔黏膜、血液、精液、卵巢等样本进行检测,有助于检出低水平嵌合现象。

ObjectiveTo investigate the genetic causes in a phenotypically normal couple with three pregnancies of trisomy 21 offspring.MethodsA retrospective analysis was conducted on a phenotypically normal couple who had three pregnancies with trisomy 21 syndrome offspring and were transferred to Shandong Provincial Maternal and Child Health Care Hospital in December 2023.Genetic analysis was performed using quantitative fluorescence polymerase chain reaction(QF-PCR),karyotype analysis,chromosome microarray analysis(CMA),and fluorescence in situ hybridization(FISH).Relevant articles up to December 31,2023,were retrieved from CNKI,Wanfang Database,Yiigle,and VIP using the terms"recurrent pregnancy","consecutive pregnancy","two pregnancies",and"trisomy 21 syndrome(Down syndrome)"in Chinese.Additionally,the English terms"recurrence or recurrent""trisomy 21 syndrome"and"Down syndrome"were used to retrieve articles from PubMed,Embase,and Web of Science.The genetic causes of recurrent pregnancies with trisomy 21 syndrome fetuses were analyzed and summarized.Results(1)Case from this hospital:Results of QF-PCR,karyotype analysis,and CMA of amniotic fluid cells in this pregnancy all indicated that the fetus had trisomy 21 syndrome.FISH tests on oral mucosal cells,decidual tissue,and urine sediment cells of the pregnant woman all indicated that she was a mosaic for trisomy 21.Additionally,QF-PCR detection of short tandem repeat(STR)loci on chromosome 21 suggested that there might be gonad mosaicism in the pregnant women,and an extra chromosome 21 in the fetus was derived from gonad mosaicism 21 trisomic cells.(2)Literature review:A total of 13 case reports with detailed records of recurrent pregnancy trisomy 21 syndrome history and related test results of both partners were retrieved,making a total of 14 cases,including seven cases each with a history of 2 and 3 trisomy 21 pregnancies.Translocation trisomy 21 was detected in each pregnancy of two cases.Of the 14 cases,five cases were only detected by peripheral blood samples of the couple,and the results were normal.The other nine cases were also detected by skin fibroblasts(six cases),ovarian tissue cells(two cases),oral mucosa cells(two cases),semen(two cases),and urinary sediment cells(one case),among which six cases indicated that one of the parents was chimeric trisomy 21,and five cases were female chimerism,one case was male chimerism.Only two cases were found to have mosaic trisomy 21 in peripheral blood sample,and the chimerism ratio was lower than that of other samples detected at the same time.In five cases,the extra chromosome 21 was found to be of maternal origin through testing of STR loci on chromosome 21.ConclusionsParental mosaicism is an important cause of recurrent pregnancies with trisomy 21 syndrome.Testing samples from skin,oral mucosa,blood,semen,and ovaries can help detect low-level mosaicism.