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.

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

“…Mutations involving the human TESCO element have not been reported as a cause of DSD, however, rearrangements involving another regulatory element, termed RevSex , located 600 kb upstream of SOX9 , are associated with both XY and XX DSD. Five cases of 46,XX testicular or ovotesticular DSD that carried duplications of this region and a familial case of 46,XY DSD that carried a deletion of the element have been reported [Benko et al, 2011;Cox et al, 2011;Vetro et al, 2011;Hyon et al, 2015]. The minimal region associated with 46,XX-SRY negative DSD has been narrowed down to a 40.7-41.9-kb element, which contains 2 predicted enhancer motifs [Hyon et al, 2015].…”

“…Five cases of 46,XX testicular or ovotesticular DSD that carried duplications of this region and a familial case of 46,XY DSD that carried a deletion of the element have been reported [Benko et al, 2011;Cox et al, 2011;Vetro et al, 2011;Hyon et al, 2015]. The minimal region associated with 46,XX-SRY negative DSD has been narrowed down to a 40.7-41.9-kb element, which contains 2 predicted enhancer motifs [Hyon et al, 2015]. There is also data suggesting that deletions of an immediately adjacent and non-overlapping region are associated with 46,XY gonadal dysgenesis [Kim et al, 2015].…”

The Role of Copy Number Variants in Disorders of Sex Development

“…It has been speculated that a deletion of this enhancer prevents upregulation of SOX9 and hence testis development in 46,XY individuals, while duplication in 46,XX patients elevates SOX9 to sufficiently high levels to override the ovarian pathway and drive the formation of (sterile) testes or ovotestes. The minimal overlap between all the patients identified has been used to define the RevSex region from 178 kb [Cox et al, 2011] to 96 kb [Vetro et al, 2011], 78 kb [Benko et al, 2011], 67 kb [Xiao et al, 2013], 41 kb [Hyon et al, 2015], and most recently to 24 kb which should contain testis specific SOX9 enhancer(s) .…”

Disorders of Sex Development with Testicular Differentiation in SRY-Negative 46,XX Individuals: Clinical and Genetic Aspects

“…Two further cases with partially overlapping 17q24.3 duplications ∼ 500 kb upstream of SOX9 presented with dissimilar phenotypes: one was an infertile male with testes, while the other was an ovotesticular DSD with ambiguous genitalia [Vetro et al, 2015]. Finally, 3 recent reports [Xiao et al, 2013;Hyon et al, 2015;Kim et al, 2015] have identified 7 further SRY -negative patients with 46,XX testicular or ovotesticular DSD, who carried duplications ranging from 68 to 83.8 kb, located ∼ 510-600 kb upstream of SOX9 , which overlapped with previously reported rearrangements and allowed refining the minimal region to a 40.7-41.9-kb element.…”