206例46,XY性发育异常患者的分子诊断和临床特点分析  

Molecular diagnosis and clinical features of 206 patients with 46,XY disorders of sexual development

作　　者：刘雪萌 赵双霞[2] 朱惠[1] 韩兵[1] 徐悦 姚海军[3] 刘阳[4] 陈燕[5] 程开祥[4] 宋怀东[2] 乔洁[1] Liu Xuemeng;Zhao Shuangxia;Zhu Hui;Han Bing;Xu Yue;Yao Haijun;Liu Yang;Chen Yan;Cheng Kaixiang;Song Huaidong;Qiao Jie(Department of Endocrinology,Shanghai Ninth People′s Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200011,China;Department of Molecular Diagnostic,Core Laboratory in Medical Center of Clinical Research,Shanghai Ninth People′s Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200011,China;Department of Urology,Shanghai Ninth People′s Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200011,China;Department of Plastic Surgery,Shanghai Ninth People′s Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200011,China;Department of Obstetrics-Gynecology,Shanghai Ninth People′s Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200011,China)

机构地区：[1]上海交通大学医学院附属第九人民医院内分泌科,200011 [2]上海交通大学医学院附属第九人民医院分子诊断科,临床医学研究中心中心实验室,200011 [3]上海交通大学医学院附属第九人民医院泌尿外科,200011 [4]上海交通大学医学院附属第九人民医院整复外科,200011 [5]上海交通大学医学院附属第九人民医院妇产科,200011

出　　处：《中华内分泌代谢杂志》2022年第9期781-788,共8页Chinese Journal of Endocrinology and Metabolism

基　　金：国家自然科学基金(81873652);上海交通大学医学院附属第九人民医院临床研究型MDT项目(201903)资助。

摘　　要：目的探讨46,XY性发育异常(DSD)患者的分子诊断方法和临床特点,加深对疾病的认识。方法采用基于多重PCR的AA芯片法和探针捕获法两种靶向二代测序技术,对2009年7月至2021年6月于上海交通大学医学院附属第九人民医院诊治的206例46,XY DSD患者进行基因检测,并对分子诊断明确患者的临床特点进行分析。结果206例患者中,同时有小阴茎、尿道下裂、隐睾三种表型的患者诊断率最高,可达75.28%。患者均有不同程度外生殖器男性化不全表现,其中小阴茎伴有尿道下裂最为常见(87.25%)。81例(39.32%)患者检测为单一基因突变,104例(50.49%)患者存在多个基因突变,21例(10.19%)患者未检测到基因突变。根据美国医学遗传学和基因组学(ACMG)指南统计致病和可疑致病比例,发现明确分子诊断的有107例,诊断率为51.94%,包括类固醇5α-还原酶2(SRD5A2)突变40例(37.38%),雄激素受体(AR)突变36例(33.64%),类固醇生成因子1(NR5A1)突变18例(16.82%),17β-羟类固醇脱氢酶3(HSD17B3)突变6例(5.61%),17α-羟化酶/17,20-裂解酶(CYP17A1)、Wilms肿瘤相关基因1(WT1)、GATA结合蛋白4(GATA4)突变各2例(1.87%),黄体生成素受体(LHCGR)突变1例(0.93%)。在81例青春期后患者中,29例有乳房发育,其中25例(86.21%)为AR突变。结论46,XY DSD患者的临床表型和分子病因复杂。靶向二代测序具有高通量、高效率、低成本的优势,尤其对遗传异质性较强的46,XY DSD病因诊断具有重要价值。Objective To investigate methods of molecular diagnosis and clinical features of 46,XY disorders of sexual development(DSD).Methods A total of 206 cases of 46,XY DSD patients,who visited the Shanghai Ninth People′s Hospital,Shanghai Jiaotong University School of Medicine,from July 2009 to June 2021,underwent AA chip based on multiplex PCR and probe-capture-targeted next-generation sequencing.Clinical features of patients with genetic diagnosis were analyzed.Results Among 206 patients,the diagnostic rate of patients with micropenis,hypospadias and cryptorchidism was the highest,up to 75.28%.Almost all patients had different degrees of undermasculinized external genitalia.The most frequent phenotype was micropenis with hypospadias(87.25%).Only one gene variant was detected in 81 patients(39.32%),multiple genetic variants were detected in 104 patients(50.49%),and no gene variant was identified in 21 patients(10.19%).107 patients had definite genetic diagnosis,with a diagnostic rate of 51.94%by adding the pathogenic and likely pathogenic ratios following the American College of Medical Genetics and Genomics(ACMG)guidelines,including 40 patients of steroid 5α-reductase type 2(SRD5A2)variants(37.38%),36 patients of androgen receptor(AR)variants(33.64%),13 patients of steroidogenic factor 1(NR5A1)variants(16.82%),6 patients of 17β-hydroxysteroid dehydrogenases 3(HSD17B3)variants(5.61%),2 patients of 17α-hydroxylase/17,20-lyase enzyme(CYP17A1),Wilms′tumor 1(WT1)and GATA binding protein 4(GATA4)variants(1.87%),and one patient of luteinizing hormone receptor(LHCGR)variant(0.93%).Gynecomastia was found in 29 of 81 postpubertal patients,of which 25(86.21%)had AR variants.Conclusions 46,XY DSD presents complex clinical manifestations and molecular etiologies.Targeted nextgeneration sequencing has the advantages of high throughput,high efficiency and low cost,which has a high value especially in etiological diagnosis of 46,XY DSD with large genetic heterogeneity.

关 键 词：性发育异常 46 XY性发育异常 靶向二代测序 分子诊断 

分 类 号：R596[医药卫生—内科学]