CONTEXT: 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.