A 46,XX Ovotesticular Disorder of Sex Development Likely Caused by a Steroidogenic Factor-1 (NR5A1) Variant

Abstract

Background: A variant in steroidogenic factor-1 (SF-1, encoded by the gene NR5A1), p.Arg92Trp, has recently been reported in multiple families with 46,XX ovotesticular or testicular disorders of sex development (DSD). This amino acid change impacts the DNA-binding domain and perturbs gonadal differentiation pathways. Methods: Whole-exome sequencing was performed on a 46,XX subject with ovotesticular DSD. Results: Exome results identified a heterozygous NR5A1 variant, p.Arg92Gln, in the 46,XX ovotesticular DSD proband. This arginine-to-glutamine change has been previously reported in the homozygous state in a 46,XY patient with gonadal and adrenal dysgenesis, though 46,XY and 46,XX heterozygous carriers of this variant have not been previously reported to have any clinical phenotype. Conclusions: The NR5A1 p.Arg92Gln variant, which has thus far only been seen in a family with 46,XY DSD, most likely contributes to the ovotesticular DSD in this case. In light of the recent reports of unrelated 46,XX subjects with testicular or ovotesticular DSD with the NR5A1 variant p.Arg92Trp, it appears that other mutations in the DNA binding domain have the potential to impact the factors determining testicular and ovarian differentiation. This case demonstrates the variability of phenotypes with the same genotype and broadens our understanding of the role of SF-1 in gonadal differentiation.

Variant analysis of the chromodomain helicase DNA‐binding protein 7 in pediatric disorders of sex development

“…Even though all the patients in this group carried CHD7 gene variants, the pathogenicity of these CHD7 variants in the sex reverse remains uncertain. Here, we present the gene results for these patients; further analyses, like those previously described for NR5A1 variants, will need to wait for additional evidence.…”

Phenotypic Variation in 46,XX Disorders of Sex Development due to the <b><i>NR5A1 </i></b>p.R92W Variant: A Sibling Case Report and Literature Review

“…Recently, another missense mutation of NR5A1 at the R92 position (R92Q) was identified to cause 46,XX DSD, suggesting the general importance of the R92 residue of NR5A1 for gonadal development and sex determination [Swartz et al, 2017]. This amino acid change likely impacts the DNA-binding domain to perturb gonadal differentiation pathways.…”

Nr5a1 suppression during the murine fetal period optimizes ovarian development by fine-tuning Notch signaling

“…The R92W variant of NR5A1 is thought to escape the suppressive action of NR0B1, a pro-ovary factor (Igarashi et al, 2017;Miyado et al, 2016;Swain et al, 1998). Our data, together with the R92W observation in mice, are at odds with the presence of testicular or ovo-testicular material in XX humans carrying the R92W variant (Baetens et al, 2016;Bashamboo et al, 2016;Igarashi et al, 2017;Miyado et al, 2016;Swartz et al, 2017). One possible explanation is that NR5A1 may be required at different threshold levels with respect to sex determination in humans and mice.…”

“…Recently, 46,XX individuals with testicular or ovo-testicular disorders/differences of sex development have been reported carrying mutations in codon 92 of NR5A1, including the R92W and R92Q mutations (Baetens et al, 2016;Bashamboo et al, 2016;Igarashi et al, 2017;Miyado et al, 2016;Swartz et al, 2017). The variant protein was thought to function in the XX gonads by escaping the suppressive action of NR0B1 (also known as DAX1), a pro-ovary factor (Igarashi et al, 2017;Miyado et al, 2016;Swain et al, 1998).…”