ESPE Abstracts

Background: Steroidogenic factor 1 (encoded by the NR5A1gene) is a transcriptional regulator of genes involved in gonadal development and steroidogenesis. Mutations in NR5A1 have been identified among the most frequently genetic causes of disorders of sex development (DSD).

Objective: To report the phenotype of 31 patients associated with 17 novel and 9 previously described NR5A1 sequence variants identified in Russian patients with 46,XY DSD.

Method: Targeted next generation sequencing (NGS) analysis with a panel of 43 genes associated with sex development was performed in 280 patients with DSD 46,XY.

Results: Among 280 patients with 46, XY DSD NR5A1 variants were found in 31 patients (11%). We identified 28 pathogenic variants, including 17 novel and 11 previously reported. 27 patients presented with abnormal genitalia at birth, 7 of whom had only slightly enlarged clitoris and gonads in labia majora. 11 patients were assigned at birth as males. 3 patients with completely female external genitalia at birth were diagnosed at puberty due to profound masculinization. None of them had Mullerian derivatives. The previously described NR5A1allelic variants c.102+1G>T and R313C were identified in two of them and a novel H24Q mutation was found in the third one. The mutation R313C was also found in the other three patients with severe undervirilized external genitalia (EMS 3-5). Only 1 of the patients showed transient adrenal insufficiency during infancy. Four of our patients, who were registered as males went through puberty with normal spontaneous virilization, adequate testes volume and penile enlargement. Two of them (age 14 and 15 y) at present have gonadotropin levels within normal range, and the other two ( 21 y and 25 y) showed slightly elevated FSH level, upper normal level of LH and lower normal level of testosterone. DNA analysis in these 4 cases showed 2 previously described (R84H and R313H) and 2 novel (G321V and c.951delC) variants in NR5A1 gene. Among 20 patients with female assignment at birth 18 underwent bilateral gonadectomy and in 2 cases gonads were left for the follow-up. During laparoscopic procedure Mullerian derivates were found in four patients. Most our patients are still in prepubertal age and will be followed further.

Conclusions: Mutations in NR5A1 gene were found in 11% cases of 46 XY DSD and 17 novel pathogenic variants were identified in our cohort. Our results contribute to the better understanding of diverse phenotypes associated with alterations in the NR5A1 gene