AR基因新变异致完全型雄激素不敏感综合征一个家系的遗传学分析及产前诊断  

Genetic analysis and prenatal diagnosis of a Chinese pedigree affected with Complete androgen insensitivity syndrome due to a novel variant of AR gene

作　　者：孟凡荣[1] 李晓洲[1] 史云芳[1] 琚端[1] 王秀艳 汪春英[1] 李雪冰[2] 余文君 王颖梅[1] 周雪霞 Meng Fanrong;Li Xiaozhou;Shi Yunfang;Ju Duan;Wang Xiuyan;Wang Chunying;Li Xuebing;Yu Wenjun;Wang Yingmei;Zhou Xuexia(Department of Gynecology and Obstetrics,Tianjin Medical University General Hospital,Tianjin Key Laboratory of Female Reproductive Health and Birth Health,Tianjin Medical University General Hospital,Tianjin 300052,China;Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment,Tianjin Lung Cancer Institute,Department of Lung Cancer Surgery,Tianjin Medical University General Hospital,Tianjin 300052,China;Department of Obstetrics and Gynecology of Pingquan Town Hospital,Chengde,Hebei 067500,China;Tianjin Key Laboratory of Injuries,Variations and Regeneration of the Nervous System,MoE Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System,Tianjin Neurological Institute,Tianjin Medical University General Hospital,Tianjin 300052,China)

机构地区：[1]天津医科大学总医院妇产科,天津市女性生殖健康与优生重点实验室,天津300052 [2]天津医科大学总医院,天津市肺癌研究所,肺部肿瘤外科,天津市肺癌转移与肿瘤微环境重点实验室,天津300052 [3]承德市平泉市平泉镇卫生院妇产科,承德067500 [4]天津医科大学总医院,天津市神经病学研究所,天津市神经损伤变异与再生重点实验室,教育部中枢创伤修复与再生重点实验室,天津300052

出　　处：《中华医学遗传学杂志》2024年第10期1206-1212,共7页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金(81901502、81972354、82172901、82273019、81572568);天津市医学重点学科(专科)建设项目(TJYXZDXK-031A、TJYXZDXK-061B);天津医科大学总医院孵育基金(ZYYFY2019022);天津市自然科学基金多元投入基金项目(21JCQNJC01440);天津市自然科学基金(22JCYBJC00280)。

摘　　要：目的探讨1个完全型雄激素不敏感综合征(CAIS)家系的临床与分子遗传学特征。方法选取2019年至2021年于天津医科大学总医院就诊的1个CAIS家系为研究对象。收集先证者相关临床资料,采集先证者及其家系成员外周血样,对先证者进行染色体核型分析、性别决定基因(SRY)检测及高通量测序(NGS),应用Sanger测序对先证者家系成员进行验证,并为先证者姐姐提供产前诊断。本研究通过天津医科大学总医院医学伦理委员会的审查(伦理号:IRB2023-WZ-070)。结果先证者现18岁,社会性别为女性,腹腔镜探查未见子宫及卵巢。外周血染色体核型为46,XY,SRY基因检测为阳性,高通量测序显示其携带AR基因c.1988C>G(p.Ser663Ter)半合子变异。经Sanger测序验证,先证者母亲及姐姐均携带该变异,其父亲与妹妹为野生型。经产前诊断,先证者姐姐第1胎为半合子变异,已终止妊娠;第2胎未携带该变异,顺产一健康男婴。根据美国医学与遗传学学会(ACMG)相关指南,该变异被判定为可能致病性(PM2_Supporting+PM4+PP3_Moderate+PP4)。结论AR基因c.1988C>G(p.Ser663Ter)变异可能是先证者CAIS的遗传学病因。对性发育不良患者的准确诊断有赖于医师对临床症状和致病基因的清晰掌握。通过基因检测和遗传咨询,可对家系成员做出准确的诊断、产前诊断及生育指导。ObjectiveTo explore the clinical and molecular basis for a Chinese pedigree affected with Complete androgen insensitivity syndrome(CAIS).MethodsA CAIS pedigree presented at Tianjin Medical University General Hospital between 2019 and 2021 was selected as the study subject.Clinical data of the proband was collected,along with peripheral blood samples from the proband and her family members.Chromosomal karyotyping,sex-determining region of the Y chromosome(SRY)testing,and next-generation sequencing(NGS)were carried out for the proband,and candidate variant was verified by Sanger sequencing of her family members.Prenatal diagnosis was provided for the sister of the proband.This study was approved by Medical Ethics Committee of the Tianjin Medical University General Hospital(Ethics No.IRB2023-WZ-070).ResultsThe 18-year-old proband,who has a social gender of female,underwent laparoscopic examination,which showed no presence of uterus and ovaries.The karyotype of peripheral blood sample was 46,XY,with SRY gene detected.NGS indicated that the proband has harbored a heterozygous c.1988C>G(p.Ser663Ter)variant of the AR gene.Sanger sequencing confirmed that her mother and sister had both harbored the same variant,whilst her father and younger sister were of the wild-type.Prenatal diagnosis revealed that her sister′s first fetus had harbored carried the same variant,which had led to termination of pregnancy.Her second fetus did not carry the variant,and a healthy boy was born.Based on guidelines from the American College of Medical Genetics and Genomics(ACMG),the variant was classified as likely pathogenic(PM2_Supporting+PM4+PP3_Moderate+PP4).ConclusionThe c.1988C>G(p.Ser663Ter)variant of the AR gene probably underlay the CAIS in the proband.The accurate diagnosis of sex development disorders will rely on the physicians′thorough understanding of the clinical symptoms and pathogenic genes.Genetic testing and counseling can enable precise diagnosis,prenatal diagnosis,and guidance for reproduction.

关 键 词：完全型雄激素不敏感综合征 AR基因 遗传咨询 产前诊断 

分 类 号：R714.5[医药卫生—妇产科学] R596[医药卫生—临床医学]