携带复杂嵌合型额外小标记染色体的特纳综合征3例胎儿的产前诊断分析

Prenatal diagnosis analysis of three cases of Turner syndrome fetuses with complex mosaic small supernumerary marker chromosomes

目的探讨采用多种遗传学检测技术对携带复杂嵌合型额外小标记染色体(sSMC)的特纳综合征胎儿进行产前诊断的价值。方法选择2022年1月至12月在郑州大学第三附属医院产前诊断中心接受羊水穿刺术进行胎儿染色体核型分析的5030例孕妇中,筛选同时携带2种复杂嵌合型sSMC的3例特纳综合征胎儿(胎儿1~3)作为研究对象。对3例胎儿采取羊水细胞G显带染色体核型分析、荧光原位杂交(FISH)、染色体微阵列分析(CMA)、基因组拷贝数变异测序(CNV-seq)等遗传学检测技术,明确其sSMC来源及嵌合情况,并对其产前诊断与孕母妊娠结局进行分析。本研究遵循的研究程序符合郑州大学第三附属医院医学伦理委员会规定,并获得该伦理委员会批准(审批文号:2023-159-01)。结果①胎儿1羊水细胞G显带染色体核型分析结果显示,其染色体核型为45,X[64]/46,X,+mar1[13]/46,X,+mar2[3]。FISH检测结果显示,胎儿1羊水细胞中52%细胞包含1个X染色体信号,48%细胞包含2个X染色体信号。CMA检测结果显示,胎儿1染色体Xp22.33p21.1和Xq22.2q28区分别存在32.32、50.93 Mb缺失,Xp21.1p11.1、Xq11.1q21.2和Xq21.2q22.2区分别存在约1.43、1.78与1.43 copies嵌合缺失。②胎儿2羊水细胞G显带染色体核型分析结果显示,其染色体核型为45,X[27]/46,X,+mar1[14]/46,X,+mar2[12]。FISH检测结果显示,胎儿2羊水细胞中88%细胞包含1个X和2个Y染色体信号,12%细胞包含1个X和1个Y染色体信号。CNV-seq检测结果显示,胎儿2染色体Yq11.222q11.23区存在7.74 Mb缺失,Yp11.31q11.221区存在约1.738 copies嵌合重复。③胎儿3羊水细胞G显带染色体核型分析结果显示,其染色体核型为45,X[60]/46,X,+mar1[11]/46,X,+mar2[6]。FISH检测结果显示,胎儿3羊水细胞中28%细胞包含1个X染色体信号,72%细胞包含2个X染色体信号。CNV-seq检测结果显示,胎儿3染色体Xp22.33p11.1和Xq22.1q28区分别存在55.60、53.50 Mb缺失,Xp11.1q13.2区存在约1.85 copies嵌合缺失,Xq13.2q22.1区存在约2.66 copies嵌合重复。④3例胎儿的2种sSMC均来源于性染色体,并且均为复杂嵌合型sSMC,均被产前诊断为复杂嵌合型特纳综合征胎儿。3例胎儿孕母及其家属接受充分的遗传咨询后,均选择人工终止妊娠。结论本研究联合运用多种遗传学检测技术确定了3例携带复杂嵌合型sSMC的特纳综合征胎儿的sSMC来源和结构,为完善其产前诊断和遗传咨询提供依据。

ObjectiveTo explore the value of applying multiple genetic testing techniques for the prenatal diagnosis of Turner syndrome fetuses with complex mosaic small supernumerary marker chromosomes(sSMC).MethodsChromosomal karyotypes of amniotic fluid samples from 5030 pregnant women who had undergone amniocentesis at the Prenatal Diagnosis Center of the Third Affiliated Hospital of Zhengzhou University from January to December 2022 were retrospectively reviewed.Three fetuses with complex mosaicism fetuses(carrying 2 types of sSMC)were selected as the study subjects.Genetic tests including G-banded chromosomal karyotyping analysis,fluorescence in situ hybridization(FISH),chromosomal microarray analysis(CMA),and copy number variation sequencing(CNV-seq)were used to clarify the origin and mosaic status of the sSMC.This study has been approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University(No.2023-159-01).ResultsG-banded chromosomal analysis of fetus 1 showed a karyotype of 45,X[64]/46,X,+mar1[13]/46,X,+mar2[3].FISH results showed that 52%of of its cells had contained one X chromosome signal,whilst 48%contained two X chromosome signals.CMA results revealed the fetus had harbored a 32.32 Mb and a 50.93 Mb deletion in Xp22.33p21.1 and Xq22.2q28 regions,respectively,in addition with mosaic deletions of approximately 1.43 copies,1.78 copies and 1.43 copies in the Xp21.1p11.1,Xq11.1q21.1 and Xq21.2q22.2 regions,respectively.The fetus 2 had a karyotype of 45,X[27]/46,X,+mar1[14]/46,X,+mar2[12].FISH results indicated that 88%of its cells contained one X chromosomes signal and two Y chromosome signals,and 12%contained signals for one X chromosomes signal and one Y chromosome signal.CNV-seq results revealed a deletion of 7.74 Mb in the Yq11.222q11.23 region and a mosaic duplication of approximately 1.738 copies in the Yp11.31q11.221 region.The fetus 3 had a karyotype of 45,X[60]/46,X,+mar1[11]/46,X,+mar2[6].FISH results showed that 28%of its cells contained one X chromosome signal,and 72%contained tow X chromosome signals.CNV-seq results revealed deletions of 55.60 Mb and 53.50 Mb in the Xp22.33p11.1 and Xq22.1q28 regions,respectively,along with a mosaic deletion of approximately 1.85 copies in the Xp11.1q13.2 region and a mosaic repeats of approximately 2.66 copies in the Xq13.2q22.1 region.The sSMCs in the 3 fetuses had all originated from sex chromosomes and were of complex mosaic type.After genetic counseling,the three couples had all opted to terminate the pregnancy.ConclusionThe combined use of multiple genetic testing techniques has determined the origin and structure of complex mosaic sSMCs and provided a basis for prenantal diagnosis and genetic counseling.