SRY – 46,XX Ovotesticular Disorder of Sex Development

1. Clinical Validity: The association between SRY and 46,XX ovotesticular disorder of sex development (OTDSD) is Refuted. In a cohort of 78 SRY-negative 46,XX TDSD/OTDSD patients, no pathogenic SRY variants were identified (0/78) and causative ZF4 WT1 variants explained ~8.97 % of cases, demonstrating lack of SRY involvement (PMID:32493750).

2. Genetic Evidence: No SRY coding or regulatory mutations have been reported in 46,XX OTDSD. The absence of SRY pathogenic alleles in XX individuals with testicular or ovotesticular DSD (0 probands) supports refutation of a direct genetic role of SRY in this condition.

3. Functional Evidence: There are no in vitro or in vivo data implicating SRY activity in XX OTDSD. Conversely, ZF4 WT1 mutants act as protestis factors in granulosa cells and murine XX models, further attributing XX testis formation to WT1 perturbations rather than SRY misexpression.

Key Take-home: SRY is not a causative gene in 46,XX OTDSD; focus should remain on alternative factors such as WT1 ZF4 variants.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2020 • Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene. PMID:32493750

Evidence Based Scoring (AI generated)