46,XY性发育异常(46,XY DSD)发病率约1/6000，以XY性染色体+不同程度女性化的生殖器为其临床特征，是研究睾丸决定和分化发育调控机制的天然人体模型。30余种致病基因突变参与其发病，但仅约40%的患者可明确病因。基因组结构变异(SV) 通过改变调控元件(如启动子和增强子)的拷贝数或影响其位置和/或功能，参与基因表达调控，导致疾病发生。至今尚无研究全面评估基因组结构变异在46,XY DSD发病中的作用。本研究拟：1.在300余例46,XY DSD患者中，通过全外显子组测序及新发/意义不明突变的体外功能验证，明确46,XY DSD患者的基因突变谱，分析它们与临床表型和预后的相关性，实现精准治疗。2.对未发现致病突变的46,XY性发育不全患者，行10xGenomics基因组重测序，明确SV发生情况，扩展对46,XY DSD病因的认识。为研究睾丸决定和分化发育调控新机制提供线索。

46,XY disorders of sex development (46,XY DSD) is the main type of disorders of sex development and its prevalence is about 1 / 6000. It is a congenital disease and characterized by XY chromosome combined with different degrees of feminization in the genitals. The patients with 46,XY DSD are natural human model that can be used to explore the mechanisms of testicular deternimation and differentiation. It is currently believed that gene mutations are the main cause of 46,XY DSD and more than 30 genes are involved in the pathogenesis of 46,XY DSD. However, gene mutations could be identified in less than 50% of patients. Genomic structural variation (SV) is involved in the regulation of genes and causes disease by altering the copy number of regulatory elements or affecting the location and/or function of cis-regulatory elements such as promoters and enhancers. To date, there has been no comprehensive evaluation on the role of SV in the pathogenesis of 46, XY DSD. This study aims to investigate the following issues: 1. To identify the gene mutation profile of 46,XY DSD patients by sequencing the whole exome of more than 300 patients with 46,XY DSD and verify the function of new mutations in vitro. The correlation between mutation profiles with clinical phenotype and prognosis was analyzed to achieve precise treatment. 2. For 46,XY DSD patients with no pathogenic mutations, a 10x Genomics re-sequencing was performed to determine the occurrence of SV which will expand the understanding of the etiology of 46, XY DSD. This research will help for prenatal genetic screening; at the same time, it will help to provide important clues for the regulation mechanism of testicular determination and differentiation.