Partial deletion of the NR5A1 (SF1) gene detected by synthetic probe MLPA in a patient with XY gonadal disorder of sex development

Steroidogenic factor 1 (SF1, officially NR5A1) is a nuclear receptor involved in adrenal and gonadal development. NR5A1 mutations have been identified in patients with various forms of 46,XY disorders of sex development (DSD), including complete gonadal dysgenesis with or without adrenal insufficiency, mild testicular dysgenesis with ambiguous external genitalia or female external genitalia with clitoromegaly, and penoscrotal hypospadias. We developed a synthetic probe set for MLPA analysis of the NR5A1 gene covering its 7 exons and analyzed 20 patients with 46,XY gonadal DSD in whom analyses failed to identify a genetic cause. We identified a partial NR5A1 deletion affecting exons 2 and 3, leading to NR5A1 haploinsufficiency in 1 patient presenting with female external genitalia with clitoromegaly, absence of a uterus, and mildly dysgenetic testes. This is the first partial NR5A1 gene deletion identified by MLPA in a patient with 46,XY gonadal DSD. This finding stresses the importance of investigating copy number changes, even at the exon level, in genes involved in gonadal DSD. As NR5A1 mutations can cause a wide spectrum of DSD with relatively high frequency, the analysis of the NR5A1 gene by MLPA is quite important and should be extended to larger groups of patients.