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Background  Dozens of genes are involved in 46, XY differences in sex development (DSD). Notably, about 3/4 of patients cannot make a clear etiology diagnosis and single gene variant identified cannot fully explain the clinical heterogeneity of 46, XY DSD.    Materials and methods  We conducted a systematic clinical analysis of a 46, XY DSD patient, and applied whole-exome sequencing for the genetic analysis of this pedigree. The identified variants were analyzed by bioinformatic analysis and in vitro studies were performed in human embryonic kidney 293T (HEK-293T) cells which were transiently transfected with wild type or variant  NR5A1  and  MAP3K1  plasmid. Furthermore, protein production of SRY-box transcription factor 9 (SOX9) was analyzed in cell lysates.    Results  A novel  NR5A1  variant (c.929A > C, p. His310Pro) and a rare  MAP3K1  variant (c.2282T > C, p. Ile761Thr) were identified in the proband, whereas the proband's mother and sister who only carry rare  MAP3K1  variant have remained phenotypically healthy to the present. These two variants were predicted to be pathogenic by bioinformatic analysis. In vitro,  NR5A1  variant decreased the SOX9 production by 82.11% compared to wild type  NR5A1 , while  MAP3K1  variant had little effect on the SOX9 production compared to wild type  MAP3K1 . Compared to wild type  NR5A1  transfection, the SOX9 production of cells transfected with both wild type plasmids decreased by about 17.40%. Compared to variant  NR5A1  transfection, the SOX9 production of cells transfected with both variant plasmids increased by the 36.64%.    Conclusions  Our findings suggested the novel compound variants of  NR5A1  and  MAP3K1  can alter the expression of SOX9 and ultimately lead to abnormality of sex development.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13023-021-01908-z.

Characteristics and possible mechanisms of 46, XY differences in sex development caused by novel compound variants in NR5A1 and MAP3K1