A novel NR 5 A 1 variant in an infant with elevated testosterone from an A ustralasian cohort of 46, XY patients with disorders of sex development

Summary Background NR 5 A 1 loss‐of‐function mutations are increasingly found to be the cause of 46, XY disorders of sex development ( DSD ). Objective To determine the presence of NR 5A1 mutations in an A ustralasian cohort of 17 46, XY DSD patients with presumed androgen insensitivity syndrome ( AIS ) who were negative for androgen receptor gene ( AR ) mutation. Design Exons 2‐7 of NR 5A1 were PCR amplified and sequenced. Gene expression and cellular localization studies were performed on a novel NR 5A1 variant c.74 A > G (p. Y 25 C ) identified in this study. Results We identified one novel mutation, c.74 A > G (p. Y 25 C ) in a patient characterized by penoscrotal hypospadias with bifid scrotum. He had elevated testosterone and gonadotropins in early infancy. Functional analysis of p. Y 25 C in vitro demonstrated reduced transcriptional activation by SF ‐1 and partially impaired nuclear localization in a proportion of transfected human adrenal NCI ‐ H 295 R cells. Conclusion This is the first reported case of a DSD patient with a NR 5 A 1 mutation and elevated testosterone levels. Our finding supports evaluation of NR 5 A 1 mutations in 46, XY DSD patients with a range of testosterone levels.