Background The XX male disorder of sex development (DSD) is a rare condition that is most commonly associated with the presence of the SRY gene on one of the X chromosomes due to unequal crossing-over between sex chromosomes during spermatogenesis. However, in about 20% of the XX male individuals, SRY is missing, although these persons have at least some testis differentiation. The genetic basis of genital ambiguity and the mechanisms triggering testis development in such patients remain unknown.
Methods The proband with 46,XX SRY-negative testicular DSD was screened for point mutations by whole exome sequencing and CNVs using a high-resolution DSD gene-targeted and whole genome array comparative genomic hybridisation. The identified Xp21.2 genomic alteration was further characterised by direct sequencing of the breakpoint junctions and bioinformatics analysis.
Results A unique, 80 kb microdeletion removing the regulatory sequences and the NR0B1 gene was detected by microarray analysis. This deletion disturbs the human-specific genomic architecture of the Xp21.2 dosage-sensitive sex (DSS) reversal region in the XX patient with male-appearing ambiguous genitalia and ovotestis.
Conclusions Duplication of the DSS region containing the MAGEB and NR0B1 genes has been implicated in testis repression and sex reversal. Identification of this microdeletion highlights the importance of genomic integrity in the regulation and interaction of sex determining genes during gonadal development.
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Contributors SAY designed the study, analysed the results of array CGH, WES and Sanger sequencing experiments. MST performed WES experiments and analysis. PD, SFW and FXS analysed the clinical and histological data. MRM performed histopathology analyses. SAY and AR performed the bioinformatics and WES analyses. PD and SAY drafted the manuscript. All authors contributed to discussion of the results and manuscript preparation.
Competing interests None declared.
Patient consent This patient has been enrolled into the study according to the Institutional Review Board 3 years ago. Unfortunately, at the present time, the patient’s family cannot be traced to obtain informed consent. Our patient, an individual with the XX chromosome complement, has an isolated sex reversal (a male-appearing genitalia). In addition, the provided clinical details, such as age on examination and ethnicity, are not sufficient for patient identification. Our manuscript does not contain the patient’s identifiable information, such as family history, physical description or facial photographs; therefore, we believe that the patient’s information is sufficiently anonymised.
Ethics approval The study was approved by the Institutional Review Board at the University of Pittsburgh (PRO14010637).
Provenance and peer review Not commissioned; externally peer reviewed.
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