title: Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene.
abstract: BACKGROUND
  Testis development is a tightly regulated process that requires an efficient and coordinated spatiotemporal action of many factors, and it has been shown that several genes involved in gonadal development exert a dosage effect. Chromosomal imbalances have been reported in several patients presenting with gonadal dysgenesis as part of severe dysmorphic phenotypes.
  
  
  RESULTS
  We screened for submicroscopic DNA copy number variations in two sisters with an apparent normal 46,XY karyotype and female external genitalia due to gonadal dysgenesis, and in which mutations in known candidate genes had been excluded. By high-resolution tiling bacterial artificial chromosome array comparative genome hybridization, a submicroscopic duplication at Xp21.2 containing DAX1 (NR0B1) was identified. Using fluorescence in situ hybridization, multiple ligation probe amplification, and PCR, the rearrangement was further characterized. This revealed a 637-kb tandem duplication that in addition to DAX1 includes the four MAGEB genes, the hypothetical gene CXorf21, GK, and part of the MAP3K7IP3 gene. Sequencing and analysis of the breakpoint boundaries and duplication junction suggest that the duplication originated through a coupled homologous and nonhomologous recombination process.
  
  
  CONCLUSIONS
  This represents the first duplication on Xp21.2 identified in patients with isolated gonadal dysgenesis because all previously described XY subjects with Xp21 duplications presented with gonadal dysgenesis as part of a more complex phenotype, including mental retardation and/or malformations. Thus, our data support DAX1 as a dosage sensitive gene responsible for gonadal dysgenesis and highlight the importance of considering DAX1 locus duplications in the evaluation of all cases of 46,XY gonadal dysgenesis.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden. Michela.barbaro@ki.se
authors.forename: Michela
authors.initials: M
authors.lastname: Barbaro
authors.forename: Mikael
authors.initials: M
authors.lastname: Oscarson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schoumans
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.forename: Sten A
authors.initials: SA
authors.lastname: Ivarsson
authors.forename: Anna
authors.initials: A
authors.lastname: Wedell
mesh_terms: D000293:Adolescent; D000328:Adult; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D019295:Computational Biology; D057137:DAX-1 Orphan Nuclear Receptor; D004247:DNA / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020440:Gene Duplication; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D004247:DNA