A novel c.64G > T (p.G22C) NR5A1 variant in a Chinese adolescent with 46,XY disorders of sex development: a case report

Abstract Background Adolescents with 46,XY disorders of sex development (DSD) face additional medical and psychological challenges. To optimize management and minimize hazards, correct and early clinical and molecular diagnosis is necessary. Case presentation We report a 13-year-old Chinese adolescent with absent Müllerian derivatives and suspected testis in the inguinal area. History, examinations, and assistant examinations were available for clinical diagnosis of 46,XY DSD. The subsequent targeting specific disease‐causing genes, comprising 360 endocrine disease-causing genes, was employed for molecular diagnosis. A novel variation in nuclear receptor subfamily 5 group A member 1 ( NR5A1 ) [c.64G > T (p.G22C)] was identified in the patient. In vitro functional analyses of the novel variant suggested no impairment to NR5A1 mRNA or protein expression relative to wild-type, and immunofluorescence confirmed similar localization of NR5A1 mutant to the cell nucleus. However, we observed decreased DNA-binding affinity by the NR5A1 variant, while dual-luciferase reporter assays showed that the mutant effectively downregulated the transactivation capacity of anti-Müllerian hormone. We described a novel NR5A1 variant and demonstrated its adverse effects on the functional integrity of the NR5A1 protein resulting in serious impairment of its modulation of gonadal development. Conclusions This study adds one novel NR5A1 variant to the pool of pathogenic variants and enriches the adolescents of information available about the mutation spectrum of this gene in Chinese population.