Phenotype-Driven Whole-Exome Sequencing 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 disorder of sex development (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 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 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.