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Variants in two key genes, <jats:italic>SRY<\/jats:italic> and its target <jats:italic>SOX9<\/jats:italic>, are an established cause of 46,XY DSD, but the genetic basis of many DSDs remains unknown. SRY-mediated <jats:italic>SOX9<\/jats:italic> upregulation in the early gonad is crucial for testis development, yet the regulatory elements underlying this have not been identified in humans. Here, we identified four DSD patients with overlapping duplications or deletions upstream of <jats:italic>SOX9<\/jats:italic>. Bioinformatic analysis identified three putative enhancers for <jats:italic>SOX9<\/jats:italic> that responded to different combinations of testis-specific regulators. All three enhancers showed synergistic activity and together drive <jats:italic>SOX9<\/jats:italic> in the testis. This is the first study to identify <jats:italic>SOX9<\/jats:italic> enhancers that, when duplicated or deleted, result in 46,XX or 46,XY sex reversal, respectively. These enhancers provide a hitherto missing link by which SRY activates <jats:italic>SOX9<\/jats:italic> in humans, and establish <jats:italic>SOX9<\/jats:italic> enhancer mutations as a significant cause of DSD.<\/jats:p>","DOI":"10.1038\/s41467-018-07784-9","type":"journal-article","created":{"date-parts":[[2018,12,10]],"date-time":"2018-12-10T13:03:52Z","timestamp":1544447032000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":171,"title":["Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2058-9812","authenticated-orcid":false,"given":"Brittany","family":"Croft","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ohnesorg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Hewitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2867-7438","authenticated-orcid":false,"given":"Josephine","family":"Bowles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5704-6865","authenticated-orcid":false,"given":"Alexander","family":"Quinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1155-0959","authenticated-orcid":false,"given":"Vincent","family":"Corbin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Pelosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn","family":"van den Bergen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6357-5392","authenticated-orcid":false,"given":"Rajini","family":"Sreenivasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Knarston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gorjana","family":"Robevska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dung Chi","family":"Vu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hutson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2405-1262","authenticated-orcid":false,"given":"Vincent","family":"Harley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Ayers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Koopman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Sinclair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,12,14]]},"reference":[{"key":"7784_CR1","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1038\/346240a0","volume":"346","author":"AH Sinclair","year":"1990","unstructured":"Sinclair, A. 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