Wu Dingwen,Wu Dehua,Zheng Jing,et al.Correlations between phenotype and monogenic mutation of 46,XY sexual development disorder[J].Journal of Clinical Pediatric Surgery,2019,18(03):191-195.[doi:10.3969/j.issn.1671-6353.2019.03.006]
46,XY性发育异常与单基因变异的相关性研究
- Title:
- Correlations between phenotype and monogenic mutation of 46,XY sexual development disorder
- Keywords:
- Gonadal Dysgenesis; 46; XY/Embryo; Genes/Genetics
- 分类号:
- R726.9;R691.1;R393
- 摘要:
- 目的 探讨46，XY性发育异常（disorders of sex development，DSD）的不同表型与单基因变异的关联性。方法 收集2018年2月至2018年11月间浙江大学医学院附属儿童医院137例临床诊断为46，XY DSD的病例，并提取外周血基因组DNA。采用液相捕获技术靶向捕获2 742个疾病基因，通过高通量测序和生物信息学方法获取基因编码区和临近10 bp区域的变异，参考ACMG分类标准进行分级。将测试病例按临床表型分为“隐睾或小睾丸、尿道下裂、小阴茎或隐匿性阴茎、多种DSD表型、性别模糊、综合征型DSD”六组。计算不同表型与基因变异对46，XY DSD的阳性检出率、辅助诊断率。结果 137例中有62例检出具备临床参考价值的变异，涉及SRD5A2、AR、NR5A1、AMH、FGFR1、PROKR2、DMRT1、MAmLD1、WT1、ZEB2、AKR1C2、CHD7、CYP17A1、DMRT2、FGD1、FRAS1、GATA4、MAP3K1、POR、SAMD9、TACR3、VANGL1、WNT5A共23个基因，综合阳性检出率为45.26%。62例中36例检出能解释临床表型的基因变异，涉及SRD5A2、AR、NR5A1、AMH、FGFR1、PROKR2、DMRT1、MAmLD1、WT1、ZEB2共10个基因，辅助诊断率为26.28%。隐睾或小睾丸、尿道下裂、小阴茎或隐匿性阴茎、多种DSD表型、性别模糊、综合征型DSD的阳性检出率分别为8.33%、26.32%、38.71%、57.14%、86.36%、66.67%，其辅助诊断率分别为0.00%、15.79%、16.13%、28.57%、63.64%、50.00%。结论 单基因变异是46，XY DSD的重要遗传学病因之一，基因变异的阳性检出率和辅助诊断率均与临床表型的多样性及严重程度呈正相关；靶向捕获疾病基因联合高通量测序可作为“性别模糊、综合征型DSD、多种DSD表型”46，XY DSD遗传学测试的首选方法。
- Abstract:
- Objective To explore the correlations between various phenotypes and monogenic mutations of 46,XY sexual development disorder (DSD) and provide valuable rationales for clinical application.Methods Genomic DNA was isolated from peripheral blood of 137 patients of 46,XY DSD.The exons of 2742 pathogenic genes were acquired by liquid phase capture technology.Variants on coding region and 10 bp around exon region of these genes were obtained by high throughput sequencing and bioinformatic analysis.And classification was performed according to the ACMG criteria.Furthermore,these patients were divided into 6 groups according to their clinical phenotypes,including cryptorchidism or small testicle,hypospadias,small penis or occult penis,multiple DSD phenotypes,hermaphroditism and DSD syndrome.Then the rate of positive findings and diagnostic yield of different groups and associated gene mutations were analyzed.Results Positive/likely positive mutations with clinical value were identified in 62/137 patients involving 23 genes with an overall positive detection rate of 45.26% (SRD5A2,AR,NR5A1,AMH,FGFR1,PROKR2,DMRT1,MAmLD1,WT1,ZEB2,AKR1C2,CHD7,CYP17A1,DMRT2,FGD1,FRAS1,GATA4,MAP3K1,POR,SAMD9,TACR3,VANGL1,WNT5A).Furthermore,the diagnostic yield of characterized disease genes among patients with 46,XY DSD was 26.28% (36/137).Those with multiple DSD phenotypes,hermaphroditism and DSD syndrome had a higher rate of positive findings with the frequencies of 57.14%,86.36% & 66.67% as well as diagnostic yield with the frequencies of 28.57%,63.64% & 50.00% respectively than those with cryptorchidism or small testicle,hypospadias,small penis or occult penis.Conclusion Monogenic mutation is an important genetic cause of 46,XY DSD.The rate of positive findings and diagnostic yield are positively correlated with the severity of 46,XY DSD phenotype.Targeted capturing plus high-throughput sequencing may be used as the preferred method for genetic testing of hermaphroditism,syndromic DSD and multiple DSD phenotypes.
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备注/Memo
收稿日期:2018-11-07。
基金项目:国家重点研发计划（编号：2018YFC1002700）；浙江省分析测试科技计划（编号：2018C3706）；浙江省医药卫生科技计划（编号：2015KYA118）
通讯作者:唐达星,Email:tangdx0206@zju.edu.cn