STARD9andCDK5RAP2– novel candidate genes for oligogenic 46,XY complete gonadal dysgenesis

46,XY gonadal dysgenesis (46,XY GD) results from disruptions in the genetic program that governs testicular differentiation during gonadal sex determination, presenting as either complete (46,XY CGD) or partial (46,XY PGD) forms. While monogenic defects account for approximately 50% of cases, recent evidence suggests an oligogenic basis for some 46,XY GD cases. In this study, we investigated a case of 46,XY CGD and performed whole-exome sequencing (WES) on the patient and her parents to explore the genetic basis of the patient’s condition. Although no pathogenic variants were identified in known 46,XY GD-associated genes, we detected rare variants in theSTARD9andCDK5RAP2genes. Previous study in mice indicate that the orthologues of these genes are highly expressed in Sertoli cells during gonadal sex determination, withCdk5rap2playing a critical role in Sertoli cell polarization. Notably, the human STARD9 and CDK5RAP2 proteins interact with each other. Structural analysis suggests that the variants in STARD9 and CDK5RAP2 may alter their protein-protein interactions. Based on these findings, we propose thatSTARD9andCDK5RAP2variants may act together to impair Sertoli cell function, leading to 46,XY CGD, consistent with an oligogenic mode of inheritance. These results suggest thatSTARD9andCDK5RAP2should be considered as candidate genes for 46,XY GD and included in genetic panels for this condition.