A hypomorphic SRD5A2 haplotype with a potential founder effect: composed of common variants in individuals with 5α-reductase type 2 deficiency from South China

作者：Xiaoyun Lei, Xu Zhou, Zifeng Cheng, Sen Zhao, Chunrong Gui, Yunting Ma, Meizhen Shi, Xianda Wei, Bobo Xie, Xin Fan, Shaoke Chen, Qiuxing Tao, Yuna Su, Dejian Yuan, Baoheng Gui · 发表于：Figshare · 年份：2026 · DOI：10.6084/m9.figshare.c.8366722 · 研究领域：Genetics、Biology

Abstract Background Disorders of sex development (DSDs) exhibit high genetic and phenotypic heterogeneity, and genotype–phenotype correlations are not fully understood. 5α-Reductase type 2 (5α-RD2) deficiency, a common form of DSD, is caused by SRD5A2 inactivation. This study investigated the role of SRD5A2 haplotypes in DSD, focusing on their corresponding phenotypes, structural changes and impacts on enzyme activity. Methods This study enrolled 216 individuals with DSD who underwent genetic analysis and 2,794 controls. Linkage disequilibrium analysis was performed in individuals with 5α-RD2 deficiency to identify SRD5A2 haplotypes, and haplotype frequencies were analysed across cohorts. The clinical manifestations of individuals with different SRD5A2 haplotypes were characterized. Structural predictions were employed to investigate the impacts of haplotypes on the 5α-RD2 structure and interactions with ligands. Functionally, kinetic assays were conducted to validate the effects of different haplotypes on enzyme activity. Results A SRD5A2 haplotype composed of c.265C > G and c.680G > A (Hap3: G-A) was identified, and the haplotype frequency was 64.71% in individuals with 5α-RD2 deficiency, 2.59% and 1.22% in non-5α-RD2 deficiency DSD cases without or with known DSD-related gene variants, respectively, and 1.57% in in-house controls. Globally, Hap3: G-A was enriched in southern Chinese individuals and showed high population differentiation, indicating a potential founde...