人类生殖系统的正常发育，对于个体青春期的发育和生殖能力的获得至关重要。从基本机制角度而言，该过程可以分为三部分：1.性别决定和性别分化，其正常进行极大程度依赖于肾上腺和性腺来源的性激素；2.下丘脑-促性腺激素细胞轴在人类胚胎中的发育；3.下丘脑-垂体-性腺（hypothalamic-pituitary-gonadal，HPG）轴在人类婴幼儿时期的发育。其中的任一过程都需要多种基因、蛋白、激素、信号分子等恰当、精细地配合才能完成。任一环节出现问题，都可能导致内外生殖器发育异常、青春发育异常、生育能力异常等表型，进而表现为相应的疾病状态。

    当促性腺激素释放激素（Gonadotropic-releasing hormone，GnRH）神经元发生孤立性缺陷时，会导致一种遗传性疾病，即先天性低促性腺激素性性腺功能减退症（Congenital hypogonadotropic hypogonadism，CHH）的发生。部分CHH患者同时有生殖系统以外的临床表型，称为综合症型CHH。CHH的遗传学病因探索是目前国内外的研究热点，也是明确该疾病基因型-表型关联、探索人类生殖系统发育机制的重要突破口。本文第一部分，分析了携带已知致病基因CHD7变异CHH患者的基因变异谱和临床表型谱，并进一步探索了新致病基因SOX11与CHH疾病的关系。

       11β-羟化酶缺陷症（11β-hydroxylase deficiency，11β-OHD）是一种由CYP11B1基因的双等位突变引起的罕见常染色体隐性遗传性疾病。CYP11B1基因双等位突变导致肾上腺类固醇生物合成缺陷，疾病特征为女性男性化、男性中枢性性早熟、高血压和低钾血症。本文的第二部分，总结了11β-OHD患者的基因变异谱和临床表型谱，并对新发现的致病意义未明的罕见变异，于细胞层面进行了功能学验证。

The intact human reproductive system is crucial for the onset of puberty and fertility in individuals. From a basic mechanism perspective, this process can consist of three parts. Firstly, gender determination and differentiation, greatly rely on the normal level of sex hormones generated by adrenal glands and gonads. Secondly, the development of the hypothalamic-pituitary-gonadal (HPG) axis in human embryos. Thirdly, the development of the HPG axis during infancy and early childhood in humans. Each of these processes requires appropriate and precise coordination of a series of genes, proteins, hormones, signaling molecules, etc. Any disruption may lead to abnormalities of the development of internal and external reproductive organs, puberty, and fertility, and subsequently manifest as corresponding disease states.

       Congenital hypogonadotropic hypogonadism (CHH) characterized by isolated defects in gonadotropin-releasing hormone (GnRH) neurons is a rare genetic disease. Some CHH patients also present with clinical phenotypes beyond the reproductive system, known as syndromic CHH. Studies of the genetic etiology of CHH are currently a cutting-edge research topic both domestically and internationally, serving as a breakthrough point to clarify the phenotype-genotype correlation of the disease and explore the developmental mechanisms of the human reproductive system. In the first part of this thesis, we analyze the spectrum of gene variants and clinical phenotypes in CHH patients carrying known pathogenic gene CHD7 rare variants (RVs) and further explore the relationship between the candidate causative gene SOX11 and CHH.

       11β-hydroxylase deficiency (11β-OHD) is a rare autosomal recessive genetic disorder caused by biallelic mutations in the CYP11B gene. Mutations in CYP11B result in defects in the biosynthesis of adrenal steroids. 11β-OHD is characterized by female virilization, male central precocious puberty, hypertension, and hypokalemia. Hence, in the second part of this thesis, we summarize the spectrum of clinical phenotypes and gene variants of 11β-OHD patients and further perform functional validation of novel RVs in CYP11B1 at the cellular level.