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Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development
  1. Sabina Benko1,2,
  2. Christopher T Gordon1,2,
  3. Delphine Mallet3,
  4. Rajini Sreenivasan4,5,
  5. Christel Thauvin-Robinet6,
  6. Atle Brendehaug7,
  7. Sophie Thomas1,2,
  8. Ove Bruland7,
  9. Michel David8,
  10. Marc Nicolino8,
  11. Audrey Labalme9,
  12. Damien Sanlaville9,
  13. Patrick Callier10,
  14. Valerie Malan11,
  15. Frédéric Huet12,
  16. Anders Molven13,14,
  17. Frédérique Dijoud15,
  18. Arnold Munnich1,2,16,
  19. Laurence Faivre6,
  20. Jeanne Amiel1,2,16,
  21. Vincent Harley4,
  22. Gunnar Houge6,17,
  23. Yves Morel3,
  24. Stanislas Lyonnet1,2,15
  1. 1INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France
  2. 2Université Paris Descartes, Faculté de Médecine, Paris, France
  3. 3Endocrinologie Moléculaire et Maladies Rares, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron, France
  4. 4Molecular Genetics and Development, Prince Henry's Institute of Medical Research, Monash Medical Centre, Clayton, Australia
  5. 5Department of Anatomy and Cell Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkvill, Australia
  6. 6Centre de Génétique, Hôpital d'Enfants, Dijon, France
  7. 7Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  8. 8Endocrinologie Pédiatrique, HFME, Hospices Civils de Lyon, Bron, France
  9. 9Cytogénétique, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron, France
  10. 10Cytogénétique, Plateforme de Biologie, CHU Dijon
  11. 11AP-HP, Service d'Histo-embryo-cytogénétique, Hôpital Necker-Enfants Malades, Paris, France
  12. 12Pédiatrie, Hôpital d'Enfants, CHU Dijon
  13. 13The Gade Institute, University of Bergen, Bergen, Norway
  14. 14Department of Pathology, Haukeland University Hospital, Bergen, Norway
  15. 15Service d'anatomopathologie, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France
  16. 16AP-HP, Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France
  17. 17Department of Clinical Medicine, University of Bergen, Bergen, Norway
  1. Correspondence to Professor Stanislas Lyonnet, Département de Génétique et Unité INSERM U-781, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, Paris cedex 15 75743, France; stanislas.lyonnet{at}


Background The early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off.

Results Through copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517–595 kb upstream of the SOX9 promoter.

Conclusions These data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.

  • Disorder of sex development
  • sox9
  • campomelic dysplasia
  • gonad
  • non-coding DNA
  • genetics
  • molecular genetics
  • reproductive medicine
  • clinical genetics
  • copy-number
  • developmental
  • epilepsy and seizures
  • cytogenetics
  • diabetes
  • cancer: dermatological
  • pancreas and biliary tract
  • paediatric oncology
  • genetic screening/counselling
  • parkinson-s disease
  • cytogenetics
  • endocrinology
  • adrenal disorders
  • other endocrinology

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  • YM and SL are senior co-authors.

  • Funding This work was supported by INSERM, ANR (MRare 2007 and EvoDevoMut 2010), the Hospices Civils de Lyon, and the NHMRC (Australia). S Benko was supported by the Fondation pour la Recherche Médicale (FRM).

  • Competing interests None to declare.

  • Patient consent Obtained.

  • Ethics approval CCP Ile-de-France II.

  • Provenance and peer review Not commissioned; externally peer reviewed.