Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9

Brittany Marie Croft, Thomas Ohnesorg, Jacqueline Hewitt, Josephine Bowles, A Quinn, J Tan, Vincent D A Corbin, Emanuele Pelosi, Jocelyn Van Den Bergen, Rajini Sreenivasan, Ingrid M. Knarston, Gorjana Robevska, Dung Chi Vu, John Hutson, Vincent Harley, Katie Ayers, Peter Koopman, Andrew Sinclair

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112 Citations (Scopus)


Disorders of sex development (DSDs) are conditions affecting development of the gonads or genitalia. Variants in two key genes, SRY and its target SOX9, are an established cause of 46,XY DSD, but the genetic basis of many DSDs remains unknown. SRY-mediated SOX9 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 SOX9. Bioinformatic analysis identified three putative enhancers for SOX9 that responded to different combinations of testis-specific regulators. All three enhancers showed synergistic activity and together drive SOX9 in the testis. This is the first study to identify SOX9 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 SOX9 in humans, and establish SOX9 enhancer mutations as a significant cause of DSD.

Original languageEnglish
Article number5319
Number of pages10
JournalNature Communications
Issue number1
Publication statusPublished - 14 Dec 2018


  • gene expression
  • gene regulation

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