Novel pathogenic mutations in disorders of sex development associated genes cause 46,XY complete gonadal dysgenesis

Disorders of sex development (DSDs) are congenital conditions in which chromosomal, gonadal and sex is atypical. It is difficult to diagnose and manage patients with DSD in clinical practice, and the molecular etiology of DSD is still not completely understood. Here, we identified two novel pathogenic mutations from three unrelated Chinese patients with 46,XY complete gonadal dysgenesis (CGD) that is a clinical subgroup of DSD by whole exome sequencing. A novel mutation in the SRY gene (c.161delG) was identified in the first patient, and the second patient carried a novel missense mutation in the MAP3K1 gene (c.2117T > G). Bioinformatics analysis found that the deletion of SRY (c.161delG) led to a premature stop codon at amino acid 59 in the SRY protein, which resulted in lacking the DNA binding domain of SRY protein. Functional studies found that the missense mutation in the MAP3K1 gene (c.2117T > G) could interfere with the gene function through increasing the phosphorylation of the downstream targets of MAP3K1, ERK1/2 and p38, which resulted in reducing testis determining factor SOX9 expression and increasing ovary-promoting factor beta-catenin activity. According to the American college of medical genetics and genomics (ACMG) standards and guidelines, these mutations were categorized as "pathogenic" mutations. Thus, our findings provide two novel pathogenic mutations associated with 46,XY CGD that can improve the etiological diagnosis for 46,XY CGD.