title: Refining the regulatory region upstream of SOX9 associated with 46,XX testicular disorders of Sex Development (DSD).
abstract: Disorders of Sex Development (DSD) are a heterogeneous group of disorders affecting gonad and/or genito-urinary tract development and usually the endocrine-reproductive system. A genetic diagnosis is made in only around 20% of these cases. The genetic causes of 46,XX-SRY negative testicular DSD as well as ovotesticular DSD are poorly defined. Duplications involving a region located ∼600 kb upstream of SOX9, a key gene in testis development, were reported in several cases of 46,XX DSD. Recent studies have narrowed this region down to a 78 kb interval that is duplicated or deleted respectively in 46,XX or 46,XY DSD. We identified three phenotypically normal patients presenting with azoospermia and 46,XX testicular DSD. Two brothers carried a 83.8 kb duplication located ∼600 kb upstream of SOX9 that overlapped with the previously reported rearrangements. This duplication refines the minimal region associated with 46,XX-SRY negative DSD to a 40.7-41.9 kb element located ∼600 kb upstream of SOX9. Predicted enhancer elements and evolutionary-conserved binding sites for proteins known to be involved in testis determination are located within this region.
authors.affiliation: AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.|INSERM UMR_S933, Paris, France.|UPMC Univ Paris 06, UFR de Médecine Pierre et Marie Curie, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Hyon
authors.affiliation: AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Chantot-Bastaraud
authors.affiliation: Service Génétique Médicale, CHU Poitiers, France.
authors.forename: Radu
authors.initials: R
authors.lastname: Harbuz
authors.affiliation: AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.
authors.forename: Rakia
authors.initials: R
authors.lastname: Bhouri
authors.affiliation: Department of Radiology, AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Tenon, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Perrot
authors.affiliation: INSERM UMR_S933, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Peycelon
authors.affiliation: Department of Pathology, AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Tenon, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sibony
authors.affiliation: Institut Pasteur, Human Developmental Genetics, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rojo
authors.affiliation: Service Endocrinologie, CHU Poitiers, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Piguel
authors.affiliation: Service Génétique Médicale, CHU Poitiers, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Bilan
authors.affiliation: Service Génétique Médicale, CHU Poitiers, France.|Centre de Référence Anomalies du Développement Ouest, CHU Poitiers, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.affiliation: Service Génétique Médicale, CHU Poitiers, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Kitzis
authors.affiliation: Institut Pasteur, Human Developmental Genetics, Paris, France.
authors.forename: Ken
authors.initials: K
authors.lastname: McElreavey
authors.affiliation: AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris, France.|INSERM UMR_S933, Paris, France.|UPMC Univ Paris 06, UFR de Médecine Pierre et Marie Curie, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Siffroi
authors.affiliation: Institut Pasteur, Human Developmental Genetics, Paris, France.
authors.forename: Anu
authors.initials: A
authors.lastname: Bashamboo
mesh_terms: D002869:Chromosome Aberrations; D012734:Disorders of Sex Development / Q000235:genetics*; D006801:Humans; D008297:Male; D012045:Regulatory Sequences, Nucleic Acid; D055758:SOX9 Transcription Factor / Q000235:genetics*
chemical_list: D055758:SOX9 Transcription Factor
keywords: 46,XX DSD; CNV; SOX9 gene; duplication; regulatory element