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This study investigated the role of\n                      <jats:italic>SRD5A2<\/jats:italic>\n                      haplotypes in DSD, focusing on their corresponding phenotypes, structural changes and impacts on enzyme activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study enrolled 216 individuals with DSD who underwent genetic analysis and 2,794 controls. Linkage disequilibrium analysis was performed in individuals with 5\u03b1-RD2 deficiency to identify\n                      <jats:italic>SRD5A2<\/jats:italic>\n                      haplotypes, and haplotype frequencies were analysed across cohorts. The clinical manifestations of individuals with different\n                      <jats:italic>SRD5A2<\/jats:italic>\n                      haplotypes were characterized. Structural predictions were employed to investigate the impacts of haplotypes on the 5\u03b1-RD2 structure and interactions with ligands. Functionally, kinetic assays were conducted to validate the effects of different haplotypes on enzyme activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A\n                      <jats:italic>SRD5A2<\/jats:italic>\n                      haplotype composed of c.265C\u2009&gt;\u2009G and c.680G\u2009&gt;\u2009A (Hap3: G-A) was identified, and the haplotype frequency was 64.71% in individuals with 5\u03b1-RD2 deficiency, 2.59% and 1.22% in non-5\u03b1-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 founder effect of the haplotype. The majority of homozygotes of Hap3: G-A presented microphallus, and nearly half of them manifested isolated microphallus. Structurally, Hap3: G-A was predicted to result in an increase in the solvent-accessible surface area (10.72 \u00c5\n                      <jats:sup>2<\/jats:sup>\n                      ), a redistribution of hydrogen bonds within 5\u03b1-RD2, and a loss of key hydrogen bonds with NADPH. Functionally, kinetic assays showed that the catalytic efficiency of the enzyme encoded by Hap3: G-A was between that of Hap1: G-G and that of Hap2: C-A.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Hap3: G-A, which is prevalent in individuals with 5\u03b1-RD2 deficiency, suggests a potential founder effect. Structurally, compared with other haplotypes, Hap3: G-A seems to have a combined effect on the structure and interaction of 5\u03b1-RD2, rather than have merely additive effects of its constituent variants. Functionally, kinetic assays suggested a hypomorphic effect of Hap3: G-A. These findings provide valuable insights for understanding genotype\u2013phenotype correlations, genetic counselling, early intervention and clinical management of individuals with 5\u03b1-RD2 deficiency or even other DSDs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13293-026-00847-3","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T12:48:14Z","timestamp":1770814094000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A hypomorphic SRD5A2 haplotype with a potential founder effect: composed of common variants in individuals with 5\u03b1-reductase type 2 deficiency from South China"],"prefix":"10.1186","volume":"17","author":[{"given":"Xiaoyun","family":"Lei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zifeng","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunrong","family":"Gui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunting","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meizhen","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianda","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bobo","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoke","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuxing","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuna","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejian","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoheng","family":"Gui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"issue":"4","key":"847_CR1","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1111\/cen.13296","volume":"86","author":"E Bennecke","year":"2017","unstructured":"Bennecke E, Thyen U, Gr\u00fcters A, Lux A, K\u00f6hler B. 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