ESPE Abstracts

The genomic analysis of 46,XX individuals with testes (known as testicular Disorders/Differences of Sex Development (TDSD) or ovotestes (ovotesticular DSD (OTDSD)) supports the hypothesis that ‘pro-testis/anti-ovary’ or ‘pro-ovary/anti-testis’ genetic pathways exist. These children typically present with virilized genitalia due to testosterone production from the presence of testicular tissue. Many individuals with TDSD and a minority with OTDSD have a translocation of the testis-determining SRY gene usually onto one of the X-chromosomes, whereas a small proportion have chromosomal rearrangements associated with upregulation (gain-of-function) of SOX gene expression. Other rare forms of 46,XX DSD can occur due to mutations (loss-of-function) involving genes in the WNT4/RSPO1 signaling pathway. However, the etiology of majority of 46,XX DSD cases remains unknown. Using unbiased high throughput sequencing approaches, we are generating evidence to support a key role for nuclear receptors as pro-ovary/anti-testis factors. In an analysis of 82 cases of 46,XX DSD cases, we identified recurrent mutations involving in the R92 residue of the nuclear receptor NR5A1 that are associated with the phenotype (P=10⁻⁷) as well as recurrent mutations in the nuclear receptor NR2F2, which encodes COUP-TF2 (genetic association P=10⁻⁸). Furthermore, we have identified both de novo mutations and rare variants in nuclear receptor cofactors, which we consider to be either pathogenic or may contribute to the development of the phenotype. This data provides further evidence of the emerging importance of nuclear receptors in specifically establishing human ovarian identity.