SRY – 46,XY Partial Gonadal Dysgenesis

SRY encodes the testis‐determining factor critical for male differentiation. Classic mutations in its HMG domain cause complete gonadal dysgenesis in 46,XY individuals (PMID:1339396; PMID:7717397). We describe a 15-year-old phenotypic female diagnosed with 46,XY partial gonadal dysgenesis carrying a de novo NM_003140.3:c.281T>G (p.Leu94Arg) missense variant in the HMG box of SRY (PMID:33457310). Parental testing and control screening excluded inheritance and polymorphism.

Structural modelling demonstrated only slight conformational change of the HMG fold, correlating with preserved partial DNA‐binding function and the intermediate dysgenesis phenotype (PMID:33457310). Genetic evidence is limited to this single case with no segregation; functional evidence is limited to in silico modelling supported by established HMG‐box variant analyses. No conflicting reports have been identified. Inclusion of SRY HMG‐box sequencing in diagnostic panels for 46,XY partial gonadal dysgenesis is recommended to inform clinical management and genetic counseling.

References

• Translational Pediatrics • 2020 • A case report of 46,XY partial gonadal dysgenesis caused by a novel mutation in the sex-determining region gene. PMID:33457310
• Human genetics • 1992 • Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. PMID:1339396
• American journal of human genetics • 1995 • Two novel SRY missense mutations reducing DNA binding identified in XY females and their mosaic fathers. PMID:7717397

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