SRD5A2基因变异致5α-还原酶2型缺乏症的临床和遗传学研究  

Clinical and genetic features of 5 alpha-reductase type2 deficiency caused by SRD5A2 gene variants

作　　者：夏俊珂 赵学潮 李泸平[2] 白周现 孔祥东[1] Xia Junke;Zhao Xuechao;Li Luping;Bai Zhouxian;Kong Xiangdong(Prenatal and Genetic Diagnosis Center,Department of Gynaecology and Obstetrics,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China;Department of Pediatric Surgery,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China)

机构地区：[1]郑州大学第一附属医院妇产科,遗传与产前诊断中心,郑州450052 [2]郑州大学第一附属医院小儿外科,郑州450052

出　　处：《中华内分泌代谢杂志》2023年第8期683-688,共6页Chinese Journal of Endocrinology and Metabolism

基　　金：国家重点研发计划(2018YFC1002203);郑州市科技惠民计划项目(2021KJHM0003)。

摘　　要：目的探讨5α-还原酶2型缺乏症(5α-RD2)的临床表型和遗传学特点。方法回顾性分析3例5α-RD2患者,总结临床资料。应用染色体核型分析、全外显子测序(WES)、Sanger测序、生物信息学分析对患者进行遗传学检测,采用SWISS-MODEL和PyMoL软件对新变异体进行蛋白质同源建模和结构分析。结果3例患者社会性别均为女。例1,6岁因外生殖器发育异常就诊。例2和3,15岁因原发闭经就诊,青春期第二性征男性化。3例患者外生殖器不同程度男性化,阴蒂肥大似小阴茎伴隐睾。例2行hCG激发试验,睾酮/双氢睾酮比值为17.4。3例患者均为46,XY核型,WES均检测到SRD5A2基因变异,基因型分别为p.Gln6Ter/p.Arg227Gln、p.Gln6Ter/p.Pro250Ala和p.Arg227Ter/p.His89Tyr,经父母验证,均为复合杂合变异。Pro250Ala为新发现的变异,根据ACMG指南评为疑似致病变异,蛋白质建模分析表明变异体可能影响5α-还原酶2型与NADPH的结合。例1选择男性性别,行腹腔镜下双侧睾丸下降固定术。例2选择女性性别,行睾丸切除术和阴道成形术。例3暂未明确选择性别。结论外生殖器发育异常是5α-RD2的常见表型,hCG激发试验后睾酮/双氢睾酮比值明显升高,可直接进行SRD5A2基因Sanger测序。5α-RD2具有显著的临床异质性,使用WES可对46,XY性发育异常疾病进行鉴别诊断。本研究还报道了Pro250Ala新变异,丰富了SRD5A2基因变异数据库。Objective To explore the clinical and genetic characteristics of 5α-reductase 2 deficiency syndrome(5α-RD2).Methods Retrospective analysis of three cases of 5α-RD2 to summarize clinical data.Genetic testing was conducted using chromosome karyotyping analysis,whole-exome sequencing(WES),Sanger sequencing,and bioinformatics analysis.The effect of the novel variant on the structure of the 5α-reductase was evaluated by studying the homology modeling structure using SWISSMODEL and PyMoL.Results The patients of all three cases have social gender as female.In Case 1,a 6-year-old patient sought medical attention due to abnormal external genitalia development.In Cases 2 and 3,15-year-old patients presented with primary amenorrhea,and they showed masculinization of secondary sexual characteristics during puberty.In all three cases,the external genitalia exhibited varying degrees of masculinization,with clitoromegaly resembling a small penis and accompanying cryptorchidism.In Case 2,an hCG stimulation test was performed,and the testosterone/dihydrotestosterone(DHT)ratio was found to be 17.4.The karyotype of all three patients was 46,XY.Whole-exome sequencing(WES)detected SRD5A2 gene variants in all cases,with genotypes being p.Gln6Ter/p.Arg227Gln,p.Gln6Ter/p.Pro250Ala,and p.Arg227Ter/p.His89Tyr,respectively.Parental validation confirmed compound heterozygous mutations in all cases.The novel variant p.Pro250Ala was identified and classified as a likely pathogenic variant according to ACMG guidelines.Protein modeling analysis indicated that this variant may affect the binding of 5α-reductase 2 to NADPH.In Case 1,male gender was chosen,and a laparoscopic bilateral orchiopexy was performed.In Case 2,female gender was chosen,and testectomy and vaginoplasty were performed.The gender selection for Case 3 has not been definitively determined yet.Conclusions Abnormal external genitalia is a common phenotype of 5α-RD2.After hCG stimulation test,there is a significant increase in the testosterone/dihydrotestosterone(DHT)ratio,wh

关 键 词：性发育异常 SRD5A2基因 5α-还原酶2型缺乏症 

分 类 号：R596[医药卫生—内科学]