Novel NR5A1 mutations found in Chinese patients with 46, XY disorders of sex development.

OBJECTIVE

To analyze nuclear receptor subfamily 5 group A member 1 (NR5A1) gene mutations in a cohort of Chinese patients with 46, XY Disorders of Sex Development (DSD).

METHODS

Sixty 46, XY DSD patients were recruited at Peking Union Medical College Hospital. Targeted next-generation and Sanger sequencing were performed to investigate pathogenic gene variants and validate NR5A1 gene variants, respectively. In silico tools and in vitro function studies were used to analyze the pathogenicity of rare variants. The clinical and endocrinological characteristics of patients with NR5A1 variants were retrospectively analyzed.

RESULTS

A total of four novel and three recurrent NR5A1 variants were identified in seven 46, XY DSD patients. These variants widely spread almost all the functional domains. Functional studies showed that novel mutations including p.S32N, p.N44del and p.G91D reduced transactivation of CYP11A1, while the other missense variant p.A168E did not impact protein function. All patients with NR5A1 rare variants had normal adrenal function and showed genital defects. Results of the genitalia examination showed female external genitalia (three patients), ambiguous external genitalia (two patients), female external genitalia with clitoromegaly (one patient), and hypospadias (one patient). All seven patients had bilateral testis and five of seven patients lacked Müllerian structures.

CONCLUSIONS

Four novel mutations in the NR5A1 gene were identified in our cohort with 46, XY DSD, expanding the spectrum of NR5A1 gene mutations. All patients with NR5A1 rare variants had normal adrenal function and showed genital defects.