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Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development
  1. Gwang-Jin Kim1,2,
  2. Elisabeth Sock3,
  3. Astrid Buchberger4,
  4. Walter Just5,
  5. Friederike Denzer6,
  6. Wolfgang Hoepffner7,
  7. James German8,
  8. Trevor Cole9,
  9. Jillian Mann10,
  10. John H Seguin11,
  11. William Zipf12,
  12. Colm Costigan13,
  13. Hardi Schmiady14,
  14. Moritz Rostásy1,
  15. Mildred Kramer1,
  16. Simon Kaltenbach1,
  17. Bernd Rösler1,
  18. Ina Georg1,15,
  19. Elke Troppmann1,
  20. Anne-Christin Teichmann1,
  21. Anika Salfelder16,
  22. Sebastian A Widholz3,
  23. Peter Wieacker17,
  24. Olaf Hiort18,
  25. Giovanna Camerino19,
  26. Orietta Radi19,
  27. Michael Wegner3,
  28. Hans-Henning Arnold4,
  29. Gerd Scherer1
  1. 1Institute of Human Genetics, University of Freiburg, Freiburg, Germany
  2. 2Faculty of Biology, University of Freiburg, Freiburg, Germany
  3. 3Institute of Biochemistry, University of Erlangen-Nürnberg, Erlangen, Germany
  4. 4Department of Cell and Molecular Biology, Institute of Biochemistry and Biotechnology, University of Braunschweig, Braunschweig, Germany
  5. 5Institute of Human Genetics, University of Ulm, Ulm, Germany
  6. 6Department of Pediatrics and Adolescent Medicine, University Hospital Ulm, Ulm, Germany
  7. 7University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
  8. 8Department of Pediatrics, Cornell University, New York, USA
  9. 9Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, Birmingham, UK
  10. 10Department of Paediatric Oncology, Birmingham Children's Hospital, Birmingham, UK
  11. 11Pediatrix Medical Group of Ohio, Columbus, Ohio, USA
  12. 12Central Ohio Pediatric Endocrinology and Diabetes Services (COPED), Columbus, Ohio, USA
  13. 13National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Dublin, Ireland
  14. 14Klinik für Gynäkologie, Charité, Frauenklinik Campus Virchow-Klinikum, Berlin, Germany
  15. 15Area of Human DNA Variability, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucia, Granada, Spain
  16. 16Department of Pediatrics, Centre for Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
  17. 17Institute of Human Genetics, Westfälische Wilhelms Universität Münster, Münster, Germany
  18. 18Department of Pediatric and Adolescent Medicine, University of Lübeck, Lübeck, Germany
  19. 19Dipartamento di Patologia Umana ed Ereditaria, Biologia Generale e Genetica Medica, Pavia, Italy
  1. Correspondence to Dr Gwang-Jin Kim Institute of Human Genetics, University of Freiburg, Breisacherstr. 33, Freiburg D-79106, Germany;{at}


Background SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia in combination with XY sex reversal. Studies in mice indicate that SOX9 acts as a testis-inducing transcription factor downstream of SRY, triggering Sertoli cell and testis differentiation. An SRY-dependent testis-specific enhancer for Sox9 has been identified only in mice. A previous study has implicated copy number variations (CNVs) of a 78 kb region 517–595 kb upstream of SOX9 in the aetiology of both 46,XY and 46,XX disorders of sex development (DSD). We wanted to better define this region for both disorders.

Results By CNV analysis, we identified SOX9 upstream duplications in three cases of SRY-negative 46,XX DSD, which together with previously reported duplications define a 68 kb region, 516–584 kb upstream of SOX9, designated XXSR (XX sex reversal region). More importantly, we identified heterozygous deletions in four families with SRY-positive 46,XY DSD without skeletal phenotype, which define a 32.5 kb interval 607.1–639.6 kb upstream of SOX9, designated XY sex reversal region (XYSR). To localise the suspected testis-specific enhancer, XYSR subfragments were tested in cell transfection and transgenic experiments. While transgenic experiments remained inconclusive, a 1.9 kb SRY-responsive subfragment drove expression specifically in Sertoli-like cells.

Conclusions Our results indicate that isolated 46,XY and 46,XX DSD can be assigned to two separate regulatory regions, XYSR and XXSR, far upstream of SOX9. The 1.9 kb SRY-responsive subfragment from the XYSR might constitute the core of the Sertoli-cell enhancer of human SOX9, representing the so far missing link in the genetic cascade of male sex determination.

  • SRY
  • SOX9
  • disorder of sex development
  • enhancer
  • long-range control

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