一个两次妊娠外生殖器畸形胎儿家系的临床遗传学分析  

Clinical genetic analysis of a family with abnormal fetal genitalia in two pregnancies

作　　者：张亚南[1] 席惠[1] 方芳 贾政军[1] 庞佳伦 邝海燕 张巍 彭莹 ZHANG Ya'nan;XI Hui;FANG Fang;JIA Zhengjun;PANG Jialun;KUANG Haiyan;ZHANG Wei;PENG Ying(Matemal and Child Health Hospital of Hurnan Province,Changsha 410008,China;不详)

机构地区：[1]湖南省妇幼保健院,长沙410008 [2]广州嘉检医学检测有限公司,广州510300

出　　处：《实用医学杂志》2023年第1期76-80,共5页The Journal of Practical Medicine

基　　金：湖南省卫计委科研课题(编号:202105032220);湖南省自然科学基金面上项目(编号:2020JJ4387)。

摘　　要：目的明确一个两次妊娠外生殖器畸形胎儿家系的遗传病因,为有效遗传咨询提供依据。方法对引产胎儿进行脐血染色体核型分析、超声检查、尸体解剖,以及CYP21A2基因突变检测并验证变异来源。结果脐血染色体核型为46,XX,inv(9)(p11q13),超声检查提示胎儿外生殖器畸形,肾上腺增大,尸检结果与超声检查一致,病检提示儿肾上腺皮质微囊性增生。CYP21A2基因突变检测结果提示引产胎儿存在30 kb大片段纯合缺失,其父母均为携带者。该基因同时检测到11个纯合变异,分别为c.92C>T(p.P31L),c.293-13C>G,c.332_339del8(p.G111Vfs*21),c.518T>A(p.I173N),c.710T>A(p.I237N),c.713T>A(p.V238E),c.719T>A(p.M240K),c.844G>T(p.V282L),c.923dupT(p.L308Ffs*6)、c.955C>T(p.Q319*)和c.1069C>T(p.R357W),这些变异遗传自胎儿的父亲和母亲,提示CYP21A2基因30 Kb纯合缺失形成CYP21A1P/CYP21A2嵌合基因,从而导致CYP21A2基因失活。结论CYP21A2基因突变是21-羟化酶缺乏症的致病原因,导致该家系两次妊娠外生殖器畸形胎儿。联合脐血染色体核型分析、产前超声检查以及尸体解剖验证,运用合适的遗传基因检测方案,明确了遗传病因,为该家系的遗传咨询和产前诊断提供了重要依据。Objective To identify the genetic etiology of a family with abnormal genital abnormal fetal genitalia in two pregnancies and to provide reference for effective genetic counseling.Methods After karyotype analysis,ultrasound examination and autopsy of cord blood were used to make a preliminary diagnosis,CYP21A2gene mutation was detected in the fetus and family members,and the source of mutation was verified.Results The karyotype of blood chromosome was 46,XX,inv(9)(p11q13).Ultrasonography showed abnormal fetal genitalia and adrenal enlargement.The results of autopsy were consistent with those of ultrasound examination,and the pathological examination showed the adrenal cortex of the fetus was microcapsule hyperplasia.Restriction fragment length polymorphism analysis of PCR-amplified fragments for the CYP21A2 gene showed the fetus had a large homozygous deletion(~30 kb),and both parents were carriers.We also identified 11 homozygous CYP21A2 gene variants in the fetus,including c.92C>T(p.P31L),c.293-13C>G,c.332339del8(p.G111Vfs*21),c.518T>A(p.I173N),c.710T>A(p.I237N),c.713T>A(p.V238E),c.719T>A(p.M240K),c.844G>T(p.V282L),c.923dupT(p.L308Ffs*6)、c.955C>T(p.Q319*)and C.1069C>T(p.R357W),which were inherited from both parents.These homozygous variants indicated the formation of CYP21A1P/CYP21A2 chimeric gene due to the 30 kb homozygous deletion,resulting in inactivated of the CYP21A2 gene.Conclusions The mutation of CYP21A2gene is the cause of 21-hydroxylase deficiency,which caused the fetus with external genital malformation in two pregnancies in this family.The combination of cord blood chromosome karyotype analysis,prenatal ultrasound and autopsy verification,and appropriate genetic testing programs clarified the cause of the genetics,providing an important basis for genetic counseling and prenatal diagnosis of the family.

关 键 词：外生殖器畸形 肾上腺皮质增生 产前诊断 染色体核型分析 CYP21A2基因 

分 类 号：R699[医药卫生—泌尿科学]