Preliminary Study On The Causes Of SRY Negative 46,XX Male Sexual Reversal

ObjectiveTo explore the pathogenesis of SRY negative 46,XX male sexual reversal.MethodsThe applied technical methods include chromosome karyotype analysis,PCR,real-time fluorescence quantitative PCR,whole exon sequencing and whole genome sequencing to detect peripheral blood of patients and their family members,and Next GENe software for data analysis.ResultsIn this family,both the phenotype and karyotype of the father were normal,with SRY gene positive and one female and two children were born.The karyotype of daughter chromosome was 46,XX and SRY gene was negative.The karyotypes of both sons were 46,XX and SRY gene negative.No pathogenic mutations were found by whole exon sequencing.After whole-genome sequencing analysis,it was found that there was a fragment duplication at 214-457 kb in the 5′ upstream regulatory region of SOX9 gene in father,with fragment size of 243 kb.The two sons have the same duplication fragment,but the daughter does not.ConclusionThe 214-457 kb duplication in the 5′ upstream regulatory region of SOX9 gene maybe the cause of disease.We speculated that duplication region might contain unknown putative core enhancer of regulatory SOX9 expression and this enhancer interact with other regulation factor of SOX9 by dosage effect,leading to the level of basic expression of SOX9 exceed the critical threshold required for testis development in female and induce SRY negative 46,XX male sex reversal.