The Natural History of a Man With Ovotesticular 46,XX DSD Caused by a Novel 3-Mb 15q26.2 Deletion Containing NR2F2 Gene.

Gonadal sex determination is a complex genetic process by which an embryonic primordium is driven to form an ovary or a testis, which requires a delicate dosage balance involving many genes. Disruption in this molecular pathway can lead to differences of sex development (DSD). Although some genetic mechanisms leading to 46,XY DSD have been elucidated, little is known about copy-number variation (CNV) causing testicular or ovotesticular 46,XX DSD. We describe a 20-year natural history of a man with SRY-negative 46,XX who was born with atypical male external genitalia, aortic coarctation, and bilateral blepharophimosis-ptosis. The molecular study identified a de novo heterozygous 3-Mb 15q26.2 deletion, a gene-poor locus containing NR2F2, which encodes the nuclear receptor COUP-TFII that is highly expressed in ovary and cardiac arteries. Immunohistochemistry confirmed the low COUP-TFII expression on his ovotestis tissue. Monosomy of 15q26.2, encompassing the NR2F2 gene, may act as a Z-factor regulating the male sex determination negatively. This finding supports a novel type of CNV resulting in DSD in an individual who developed male puberty spontaneously.

Genetic mechanisms leading to primary amenorrhea in balanced X-autosome translocations.

OBJECTIVE: To map the X-chromosome and autosome breakpoints in women with balanced X-autosome translocations and primary amenorrhea, searching candidate genomic loci for female infertility. DESIGN: Retrospective and case-control study. SETTING: University-based research laboratory. PATIENT(S): Three women with balanced X-autosome translocation and primary amenorrhea. INTERVENTION(S): Conventional cytogenetic methods, genomic array, array painting, fluorescence in situ hybridization, and quantitative reverse transcription-polymerase chain reaction. MAIN OUTCOME MEASURE(S): Karyotype, copy number variation, breakpoint mapping, and gene expression levels. RESULT(S): All patients presented with breakpoints in the Xq13q21 region. In two patients, the X-chromosome breakpoint disrupted coding sequences (KIAA2022 and ZDHHC15 genes). Although both gene disruptions caused absence of transcription in peripheral blood, there is no evidence that supports the involvement of these genes with ovarian function. The ZDHHC15 gene belongs to a conserved syntenic region that encompasses the FGF16 gene, which plays a role in female germ line development. The break in the FGF16 syntenic block may have disrupted the interaction between the FGF16 promoter and its cis-regulatory element. In the third patient, although both breakpoints are intergenic, a gene that plays a role in the DAX1 pathway (FHL2 gene) flanks distally the autosome breakpoint. The FHL2 gene may be subject to position effect due to the attachment of an autosome segment in Xq21 region. CONCLUSION(S): The etiology of primary amenorrhea in balanced X-autosome translocation patients may underlie more complex mechanisms than interruption of specific X-linked candidate genes, such as position effect. The fine mapping of the rearrangement breakpoints may be a tool for identifying genetic pathogenic mechanisms for primary amenorrhea.