title: Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3.
abstract: Duplications in the ~2 Mb desert region upstream of SOX9 at 17q24.3 may result in familial 46,XX disorders of sex development (DSD) without any effects on the XY background. A balanced translocation with its breakpoint falling within the same region has also been described in one XX DSD subject. We analyzed, by conventional and molecular cytogenetics, 19 novel SRY-negative unrelated 46,XX subjects both familial and sporadic, with isolated DSD. One of them had a de novo reciprocal t(11;17) translocation. Two cases carried partially overlapping 17q24.3 duplications ~500 kb upstream of SOX9, both inherited from their normal fathers. Breakpoints cloning showed that both duplications were in tandem, whereas the 17q in the reciprocal translocation was broken at ~800 kb upstream of SOX9, which is not only close to a previously described 46,XX DSD translocation, but also to translocations without any effects on the gonadal development. A further XX male, ascertained because of intellectual disability, carried a de novo cryptic duplication at Xq27.1, involving SOX3. CNVs involving SOX3 or its flanking regions have been reported in four XX DSD subjects. Collectively in our cohort of 19 novel cases of SRY-negative 46,XX DSD, the duplications upstream of SOX9 account for ~10.5% of the cases, and are responsible for the disease phenotype, even when inherited from a normal father. Translocations interrupting this region may also affect the gonadal development, possibly depending on the chromatin context of the recipient chromosome. SOX3 duplications may substitute SRY in some XX subjects.
authors.affiliation: Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Vetro
authors.affiliation: 1] Department of Molecular Medicine, University of Pavia, Pavia, Italy [2] Reproductive Science Institute, Yazd University of Medical Sciences, Yazd, Iran.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Dehghani
authors.affiliation: Department of Congenital and Hereditary Diseases, Charles Nicolle Hospital, Tunis, Tunisia.
authors.forename: Lilia
authors.initials: L
authors.lastname: Kraoua
authors.affiliation: Molecular Biology Laboratory, Scientific Institute Eugenio Medea, IRCCS, Bosisio Parini (LC), Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giorda
authors.affiliation: Molecular Biology Laboratory, Scientific Institute Eugenio Medea, IRCCS, Bosisio Parini (LC), Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Beri
authors.affiliation: Laboratorio Analisi CITOTEST, Consorzio GENiMED, Sarmeola di Rubano (PD), Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cardarelli
authors.affiliation: Endocrinologic Unit, San Giacomo Hospital, Castelfranco Veneto (TV), Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Merico
authors.affiliation: Eurogenetica S.A., Laboratory of Genetics, Athens, Greece.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Manolakos
authors.affiliation: Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile.
authors.forename: Alexis
authors.identifier: 0000000232404961
authors.initials: A
authors.lastname: Parada-Bustamante
authors.affiliation: Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile.
authors.forename: Andrea
authors.initials: A
authors.lastname: Castro
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Orietta
authors.initials: O
authors.lastname: Radi
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Camerino
authors.affiliation: Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
authors.affiliation: Department of Andrology at Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Tehran, Iran.
authors.forename: Marjan
authors.initials: M
authors.lastname: Sabaghian
authors.affiliation: Department of Medical Genetics, Agia Sofia Hospital, Athens, Greece.
authors.forename: Crystalena
authors.initials: C
authors.lastname: Sofocleous
authors.affiliation: Division of Medical Genetics, Galliera Hospital, Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Forzano
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Palumbo
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
authors.forename: Orazio
authors.identifier: 0000000165833482
authors.initials: O
authors.lastname: Palumbo
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
authors.forename: Savino
authors.initials: S
authors.lastname: Calvano
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Zelante
authors.affiliation: Department of Molecular Medicine, Medical Genetics, San Camillo-Forlanini Hospital, Sapienza University, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Grammatico
authors.affiliation: Medical Genetics Section, Department of Clinical Pathophysiology, University of Florence, Florence, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giglio
authors.affiliation: Department of Obstetrics and Gynecology, Military Hospital, Tunis, Tunisia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Basly
authors.affiliation: Department of Congenital and Hereditary Diseases, Charles Nicolle Hospital, Tunis, Tunisia.
authors.forename: Myriam
authors.initials: M
authors.lastname: Chaabouni
authors.affiliation: Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.affiliation: Department of Pediatrics, Endocrine Unit, University Vita-Salute, San Raffaele Hospital, Milano, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Russo
authors.affiliation: Cytogenetics Laboratory, Scientific Institute Eugenio Medea, IRCCS, Bosisio Parini (LC), Italy.
authors.forename: Maria Clara
authors.initials: MC
authors.lastname: Bonaglia
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
mesh_terms: D058489:46, XX Disorders of Sex Development / Q000235:genetics* / Q000503:physiopathology; D000328:Adult; D056905:Chromosome Breakpoints; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D055758:SOX9 Transcription Factor / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D013737:Testis / Q000254:growth & development* / Q000473:pathology; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: C490906:SOX1 protein, human; C527785:SOX3 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D055748:SOXB1 Transcription Factors