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

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. © 2015 Wiley Periodicals, Inc.