Background: Differences/disorders of sex development (DSD) occur in approximately 1% of live births and involve disruptions in chromosomal, gonadal, or genital development. Patients with DSD often experience lengthy and inconclusive diagnostic processes, highlighting the pressing need for more effective genetic diagnostics. Specifically, the diagnostic yield for 46,XY gonadal dysgenesis leading to male-to-female sex reversal, is notably low, at only 30%.
Aim: To identify novel genetic variants associated with 46,XY DSDs to improve the genetic diagnostic yield and provide better management options for affected individuals.
Methods: Whole exome sequencing (WES) was performed to identify potential genes/variants. Then, we conducted the luciferase assays by utilizing the HEK293T cells to validate the effect of variants.
Results: The Clinical phenotype of a patient in this study is a 46,XY DSD female who presented with perineal hypospadias, clitoromegaly, and cryptorchidism. The WES data revealed the compound heterozygote variants in the doublesex and mab-3-related transcription factor 3 (DMRT3) gene. Functional analysis using luciferase reporter assays indicated that these DMRT3 variants significantly enhanced the activation of the estrogen receptor 1 (ESR1) promoter compared to the wild type in HEK293T cells. This data suggests a potential regulatory role of DMRT3 in ESR1 expression.
Conclusion: Our preliminary findings suggest that DMRT3 variants in 46,XY DSD might act in a gain-of-function manner to activate the ovarian estrogen signalling pathway by stimulating ESR1 expression. Further studies to determine whether feminisation of the 46,XY gonad and/or antagonism of the fetal testis development program are underway. This finding offers new insights into the genetic mechanisms underlying 46,XY DSDs. These results could contribute to improved genetic diagnosis and therapeutic strategies for individuals with DSD.