5α-RD2缺乏症患者外生殖器男性化不足表型高度可变，其基因型-表型关联性尚不明确。我们前期多中心大样本量病例队列研究发现5α-RD2缺乏症致病基因SRD5A2特定变异与尿道下裂严重程度相关，深入分析发现SRD5A2特定单体型与5α-RD2缺乏症发病风险相关，可通过潜在亚效等位基因效应影响患者表型差异。本项目拟从回顾性病例队列、细胞模型、动物模型及前瞻性病例队列四个层面开展研究：回顾性分析明确亚效等位单体型频谱特征；构建细胞模型鉴定亚效等位单体型调控5α-RD2活性并影响雄激素代谢通路的分子基础；建立小鼠模型阐明亚效等位单体型单位点时空差异化表达影响5α-RD2缺乏症表型差异的机制；前瞻性分析验证亚效等位单体型与表型的关联性。本研究有望阐明SRD5A2表达调控新机制、革新对5α-RD2缺乏症表型差异及基因型-表型关联性的现有认识，为有效指导临床诊治、预后管理及遗传咨询提供理论依据和新思路。

Patients with the 5α-reductase type 2 (5α-RD2) deficiency present highly variable phenotype of external genitalia undervirilization, and the genotype-phenotype correlation among the patients has still not been definitively uncovered. Our previous study based on large-scale cohort from multiple centers has revealed the possible correlation between specific variants of the disease-causing gene, SRD5A2 and the severity of hypospadias in the patients. Further analysis indicated that the specific haplotype of the SRD5A2 gene was related to the risk of 5α-RD2 deficiency, and could affect the phenotypic variability of the patients by the potential hypomorphic allele effect. The current study is aiming at discovering the function and molecular mechanism of the hypomorphic haplotypes from the aspect of clinical retrospective cohort analysis, cell line model, animal model and clinical prospective cohort analysis: the retrospective cohort study on SRD5A2 hypomorphic haplotypes to determine their frequency and spectrum; the investigation on artificial cell lines to identify the molecular basis in regulating 5α-RD2 activity and androgen synthesis and metabolism pathway by the hypomorphic haplotypes; the establishment of mouse model to discover the molecular mechanism that the spatio-temporal monoallelic expression of the hypomorphic haplotypes regulate the phenotypic variability; and the prospective cohort study on hypomorphic haplotypes and clinical manifestations to validate the relationship between these haplotypes and the phenotypes. This study is expected to elucidate the novel regulation mechanism of SRD5A2 expression and renew the current understanding of the phenotypic variability and the genotype-phenotype correlation of 5α-RD2, and further, to provide theoretical basis and new insights into the effective clinical diagnosis and therapy, prognosis and management, as well as genetic counseling for the disease.