一例成骨不全家系致病变异的鉴定及胚胎植入前遗传学检测  

Identification of pathogenic variant and preimplantation genetic testing for a Chinese family affected with osteogenesis imperfecta

作　　者：李闯 侯瑞 刘彩霞[1] 李欢[1] 李岭 吕远[1] Li Chuang;Hou Rui;Liu Caixia;Li Huan;Li-Ling Jesse;Lyu Yuan(Department of Gynecology and Obstetrics,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province,Shengjing Hospital Affiliated to China Medical University,Shenyang,Liaoning 110004,China;Department of Medical Genetics,West China Second Hospital,Sichuan University,Chengdu,Sichuan 610041,China)

机构地区：[1]中国医科大学附属盛京医院妇产科辽宁省母胎医学重点实验室,沈阳110004 [2]四川大学华西第二医院遗传科,成都610041

出　　处：《中华医学遗传学杂志》2022年第1期21-25,共5页Chinese Journal of Medical Genetics

基　　金：国家重点研发计划(2018YFC1002900);国家自然科学基金(81701462,81501260);中央引导地方科技发展专项资金(2016007014);盛京自由研究者基金(201501)。

摘　　要：目的明确一例成骨不全(osteogenesis imperfecta,OI)家系的致病变异并为其提供胚胎植入前遗传学检测(preimplantation genetic testing,PGT)。方法应用高通量测序结合Sanger测序的方法鉴定患者的候选变异,用直接检测变异的方法对胚胎进行PGT检测,同时筛查囊胚的染色体非整倍体情况。在孕期对胎儿羊水样本进行染色体检查和基因诊断。在分娩后对胎盘的不同部位进行染色体检测。结果先证者携带COL1A1基因c.544-2A>G杂合变异,其双亲均未查见同样的变异。PGT检测提示,该家系的3个囊胚中,1个为纯合野生型,但携带有16p13.3-11.2区重复(嵌合体),其余两个胚胎均携带杂合变异。经遗传咨询后,移植纯合野生型囊胚,羊水检测结果提示胎儿染色体正常且未携带致病变异。胎盘不同部位的染色体拷贝数变异检测提示拷贝数正常。结论对于患有单基因病的家系,在明确其致病变异后,可用直接检测变异位点的方法进行PGT检测,之后必须进行产前诊断。Objective To identify the pathogeic variant for a husband with osteogenesis imperfecta and provide preimplantation genetic testing(PGT)for the couple.Methods High-throughput sequencing and Sanger sequencing were carried out to identify the pathologic variant in the husband patients.PGT of embryos was performed through direct detection of the mutation site.Meanwhile,chromosome aneuploidy of the blastocysts was screened.Following transplantation,cytogenetic and genetic testing of fetal amniotic fluid sample was carried out during mid-pregnancy.Chromosome copy number variant(CNV)was detected at multiple sites of the placenta after delivery.Results The husband was found to harbor heterozygous c.544-2A>G variant of the COL1A1 gene.The same variant was not detected in either of his parents.PGT revealed that out of three embryos of the couple,one was wild-type for the c.544-2A site but mosaicism for duplication of 16p13.3-11.2.The other two embryos were both heterozygous for the c.544-2A>G variant.Following adequate genetic counseling,the wild-type embryo was transplanted.Amniotic fluid testing confirmed that the fetus had normal chromosomes and did not carry the c.544-2A>G variant.The copy number of chromosomes at different parts of placenta was normal after birth.Conclusion For couples affected with monogenic disorders,e.g.,osteogenesis imperfecta,direct detection of the mutation site may be used for PGT after identifying the pathogenic variant.After adequate genetic counseling,prenatal diagnosis must be carried out to ensure the result.

关 键 词：成骨发育不全 COL1A1基因 变异 嵌合体 植入前遗传学检测 

分 类 号：R714.5[医药卫生—妇产科学] R440[医药卫生—临床医学]