Similar Cause, Different Phenotype: SOX9 Enhancer Duplication in a Family

Introduction: 46,XX ovotesticular disorder of sex development (DSD), as defined by the Chicago consensus in 2006, is characterized by histologically confirmed testicular and ovarian tissue in an individual with a 46,XX karyotype and a wide phenotypic spectrum from female to male appearance.

Case presentation: We report the case of two 46,XX sex determining region Y (SRY) gene-negative siblings and their 46,XY father with an approximately 150 kilobase pair (kbp) duplication upstream of SOX9 (SRY-box 9) gene's transcriptional start site on chromosome 17 (chr17), which involved SOX9's minimal critical 46,XX sex reversal region. This duplication is sufficient to trigger male development in the absence of Y-chromosomal material and can lead to various degrees of masculinization in 46,XX individuals by overexpression of SOX9. Based on anamnestic information and pedigree analysis, another possible carrier of this copy number variation (CNV) could have been the father's sister.

Discussion: By comparing the duplications of our two sibling patients and previously reported similar cases, we suggest that the small differences between their breakpoints could alternatively modify the inner structure and functioning of SOX9'stopologically associated domain (TAD) due to the differing fine TAD arrangements. Our data support the phenotypic modularity impact - incomplete penetrance and variable expressivity - of very similar but non-identical CNVs, which are possibly inherited across three generations.