title: 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.
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Swartz
authors.forename: Ryan
authors.initials: R
authors.lastname: Ciarlo
authors.forename: Michael H
authors.initials: MH
authors.lastname: Guo
authors.forename: Aser
authors.initials: A
authors.lastname: Abrha
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weaver
authors.forename: David A
authors.initials: DA
authors.lastname: Diamond
authors.forename: Yee-Ming
authors.initials: YM
authors.lastname: Chan
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
mesh_terms: D058489:46, XX Disorders of Sex Development / Q000235:genetics* / Q000473:pathology; D019943:Amino Acid Substitution; D002675:Child, Preschool; D005260:Female; D006801:Humans; D020125:Mutation, Missense; D050090:Ovotesticular Disorders of Sex Development / Q000235:genetics* / Q000473:pathology; D000072417:Protein Domains; D054339:Steroidogenic Factor 1 / Q000235:genetics*
chemical_list: C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1