Phenotype-Driven WES Reanalysis Identifies a Homozygous PPP2R3C Variant in Syndromic 46,XY and 46,XX Gonadal Dysgenesis: Case Report and Review of the Literature

Introduction: PPP2R3C-related syndromic gonadal dysgenesis is a rare DSD characterized by gonadal failure, extragonadal anomalies, and a recognizable facial gestalt, reported in both 46,XY and 46,XX individuals. We report two siblings with myoectodermal gonadal dysgenesis syndrome (MEGD) due to homozygous PPP2R3C variants, diagnosed through phenotype-driven reanalysis of whole-exome sequencing (WES). Case presentation: We describe two siblings with syndromic gonadal dysgenesis who were diagnosed through phenotype-driven reanalysis of whole-exome sequencing (WES). The index patient, a 14-year-old phenotypic female with a 46,XY karyotype, presented with complete gonadal dysgenesis, renal agenesis, congenital heart disease, hearing loss, and intellectual disability. Her 8-year-old sister, with a 46,XX karyotype, showed ovarian dysgenesis, renal agenesis, and a similar craniofacial gestalt. Both carried a homozygous PPP2R3C c.1049T>C (p.Phe350Ser) variant, which was initially missed on routine WES but identified upon targeted reanalysis guided by their clinical features. Conclusion: These cases highlight the rarity of PPP2R3C-related syndromic gonadal dysgenesis and provide further evidence that the condition affects both chromosomal sexes. Our findings underscore the diagnostic importance of combining detailed phenotyping—including appreciation of distinctive facial gestalt—with systematic WES reanalysis. This approach is particularly valuable in unresolved syndromic DSD, where variable expressivity may obscure recognition of the underlying genetic defect.