SOX3 – 46,XX Ovotesticular Disorder of Sex Development

Two SRY-negative siblings, a 46,XX male with confirmed ovotesticular disorder of sex development and his 46,XX sister with atypical genitalia, were found to harbor a 737-kb duplication at Xq27.1 encompassing the entire SOX3 locus. Chromosome microarray analysis and quantitative real-time PCR confirmed the duplication, while whole-exome sequencing was negative for pathogenic coding variants, and X-chromosome inactivation was random, suggesting germline mosaicism in the parents (PMID:36416214).

The duplication segregates with the 46,XX ovotesticular phenotype in a gain-of-function, X-linked dosage-sensitive manner. Overexpression of SOX3 in XX individuals likely disrupts normal sex-determining gene networks, driving variable DSD presentations from ovotestes to ovarian dysgenesis. Although functional assays are limited to expression confirmation in patient samples, the concordant genotype–phenotype in two siblings provides evidence of pathogenicity. No additional families have been reported to date, underscoring the need for further case series and experimental modeling. Key take-home: Screening for SOX3 copy-number gains should be incorporated in the diagnostic evaluation of SRY-negative 46,XX DSD.

References

• American journal of medical genetics. Part A • 2023 • SOX3 duplication in a boy with 46,XX ovotesticular disorder of sex development and his 46,XX sister with atypical genitalia: Probable germline mosaicism. PMID:36416214

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