中国性发育异常患儿临床表型与基因型分析

Analysis of clinical phenotype and genotype of Chinese children with disorders of sex development

目的探讨性发育异常(DSD)患儿临床表型及基因型的异质性及相关性。方法回顾性分析全国36家儿童医疗机构2017年1月至2021年5月临床拟诊DSD的1235例患儿的临床资料,对277个DSD相关候选基因进行捕获之后进行二代测序,结合临床表型分析其异质性及相关性。结果1235例临床拟诊为DSD的患儿初诊时社会性别男980例、女255例,初诊年龄为1日龄至17.92岁。通过基因分子学检测致病性变异患儿共443例,阳性检出率为35.9%。临床表型以小阴茎(455例)、尿道下裂(321例)、隐睾(172例)常见;基因检测发现常见变异为SRD5A2变异(80例),AR变异(53例)及CYP21A2变异(44例)。其中临床表型为单纯小阴茎和单纯尿道下裂患儿中,均表现为SRD5A2变异最常见(分别为33例及11例),而单纯隐睾患儿中,以AMH变异最常见(7例)。结论中国DSD患儿最常见的基因变异是SRD5A2变异,常见的临床表型是小阴茎、隐睾、尿道下裂。分子诊断可以提供有关DSD生物学基础的线索并指导临床医生进行特定的临床检查,目标序列捕获探针并二代测序技术能针对性地为DSD患儿提供有效而经济的遗传学诊断。

Objective To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development(DSD).Methods A retrospective study of 1235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021.After capturing 277 DSD-related candidate genes,second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes.Results Among 1235 children with clinically proposed DSD,980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years.A total of 443 children with pathogenic variants were detected through molecular genetic studies,with a positive detection rate of 35.9%.The most common clinical phenotypes were micropenis(455 cases),hypospadias(321 cases),and cryptorchidism(172 cases)and common mutations detected were in SRD5A2 gene(80 cases),AR gene(53 cases)and CYP21A2 gene(44 cases).Among them,the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias,while the AMH mutation is the most common in children with simple cryptorchidism.Conclusions The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD,and micropenis,cryptorchidism,and hypospadias are the most common clinical phenotypes.Molecular diagnosis can provide clues about the biological basis of DSD,and can also guide clinicians to perform specific clinical examinations.Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.