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Most of the SVs found in OT-DSD individuals are whole-gene duplications, and to date, only one SV affecting\n                    <jats:italic>SOX3<\/jats:italic>\n                    expression by a positional effect has been described. We report an individual raised as a female with\n                    <jats:italic>SRY-<\/jats:italic>\n                    negative OT-DSD. Karyotype analysis showed a pericentric inversion in one of the X chromosomes \u2212\u200946,X, inv(X)(p22;q27). The breakpoints and fusion were mapped using optical genome mapping (OGM) and short-read whole genome sequencing. One of the breakpoints was mapped on Xq27.1 (genomic position chrX:140,420,874 \u2013 GRCh38), 82\u00a0kb downstream of the\n                    <jats:italic>SOX3<\/jats:italic>\n                    gene. This breakpoint was predicted to interrupt a topological associate domain (TAD) affecting 24 enhancer-promoter interactions of\n                    <jats:italic>SOX3<\/jats:italic>\n                    . RNA sequencing (RNA-seq) of a formalin-fixed paraffin-embedded (FFPE) sample of the gonads confirmed increased\n                    <jats:italic>SOX3<\/jats:italic>\n                    expression. The present study is the first to analyze gene expression in gonadal tissues from an OT-DSD individual, and the first reporting an inversion-based mechanism leading to XX OT-DSD. Additionally, an X-inactivation assay on DNA extracted from the gonads revealed random inactivation. These findings support the hypothesis that inappropriate\n                    <jats:italic>SOX3<\/jats:italic>\n                    expression may result from the positional effects of SVs, leading to OT-DSD in 46,XX individuals.\n                  <\/jats:p>","DOI":"10.1186\/s13293-025-00822-4","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T06:04:29Z","timestamp":1770876269000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Overexpression of SOX3 due to an X chromosome inversion leading to ovotesticular difference in sex development"],"prefix":"10.1186","volume":"17","author":[{"given":"Carolina Gama","family":"Nascimento-Vidoti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Fabbri-Scallet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara Sanches","family":"Guaragna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa Bittencourt","family":"de Wallau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Sodr\u00e9","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Souza","family":"da Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Cristina Victorino","family":"Krepischi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana Forte","family":"Mazzeu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia M. 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