title: Two Unrelated Undervirilized 46,XY Males with Inherited NR5A1 Variants Identified by Whole-Exome Sequencing.
abstract: BACKGROUND
  Undervirilized 46,XY males with bifid scrotum often pose a diagnostic challenge, and the majority of cases typically do not receive a genetic diagnosis. NR5A1 mutations can be seen in 10-20% of the cases and are a relatively common cause of undervirilization.
  
  
  METHODS
  Whole-exome sequencing was utilized to study 10 undervirilized 46,XY subjects with bifid scrotum.
  
  
  RESULTS
  Exome sequencing identified novel NR5A1 variants, both affecting exon 7, in 2 of the 10 subjects with bifid scrotum. Subject 1 had a heterozygous frameshift variant, c.1150delC, p.Leu384fsTer1, within the ligand-binding domain inherited from his unaffected father. Subject 2 had a novel splice-site variant c.1139-2T>C, affecting the canonical splice acceptor site for exon 7 and also disrupting the ligand-binding domain. Both subjects had serum testosterone levels within the normal range as infants.
  
  
  CONCLUSIONS
  We describe two novel NR5A1 variants, demonstrating mutations in this gene as a common cause of milder cases of 46,XY undervirilization. Whole-exome sequencing results yielded the diagnosis in 2 out of 10 cases without a previous diagnosis, supporting the value of this approach. Significant genotype-phenotype variability was also noted with Subject 1's paternal inheritance from his unaffected father.
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, Mass., 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: 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 / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D022821:RNA Splice Sites; D054339:Steroidogenic Factor 1 / Q000235:genetics*; D013739:Testosterone / Q000097:blood*
chemical_list: C515057:NR5A1 protein, human; D022821:RNA Splice Sites; D054339:Steroidogenic Factor 1; D013739:Testosterone
keywords: <italic>NR5A1</italic>; Bifid scrotum; Disorders of sex development; Exome sequencing; Undervirilization