Refining the regulatory region upstream of SOX9 associated with 46,XX testicular disorders of Sex Development (DSD).

Capucine Hyon,Xavier Piguel,Sandra Chantot‐Bastaraud,Radu Harbuz,Frederic Bilan,Ken Mcelreavey,Nicolas Perrot,Brigitte Gilbert‐Dussardier,Sandra Rojo,Anu Bashamboo,Matthieu Peycelon,Alain Kitzis,Rakia Bhouri,Jean‐Pierre Siffroi,Mathilde Sibony

doi:10.1002/ajmg.a.37101

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.

Highlights

Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical [Hughes et al, 2006]
(46,XX,dup(17)(q23.1q24.3)/46,XX) involving SOX9 was associated with female to male sex reversal in a 46,XX individual [Huang et al, 1999], mutations or translocations involving the TESCO region have not yet been reported [Georg et al, 2010]
This suggests that in human gonad additional regulatory elements may be involved in the regulation of SOX9 expression

Summary

Introduction

Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical [Hughes et al, 2006]. The detailed analyses of these patients and the incorporation of the published datasets have enabled the minimal critical region located ~600 kb upstream of SOX9 to be resolved to an approximately 40kb element that contains putative enhancers elements and DNA-binding sites for known factors to be involved in early testis formation.

Results

Conclusion