Convergent Genetic Architecture in Concurrent Anorectal Malformations and Hypospadias: The ESRRA-STARD8 Axis as a Key Regulator of Urogenital Development.

BACKGROUND

Anorectal malformations (ARM) and hypospadias are common congenital anomalies that occasionally co-occur, suggesting shared developmental pathways. Despite their clinical significance, the genetic etiology of combined ARM-hypospadias remains poorly understood.

OBJECTIVE

The objective of this study was to identify genetic variants underlying concurrent ARM and hypospadias using whole exome sequencing and elucidate the molecular mechanisms driving their co-occurrence.

MATERIALS AND

METHODS

Six boys with concurrent ARM and hypospadias underwent whole exome sequencing. Variants were filtered using stringent bioinformatic criteria (Minor Allele Frequency (MAF) <0.05, Combined Annotation Dependent Depletion (CADD) >20) and analyzed for pathogenicity using multiple prediction tools. Gene enrichment analysis, protein-protein interaction networks, and tissue expression profiles were evaluated. All patients had normal 46, XY karyotypes.

RESULTS

Five patients harbored a recurrent heterozygous missense variant in ESRRA (c.1162C>T; p.Leu388Phe), whereas the sixth patient carried a Hemizygous STARD8 variant (c.2950C>T; p.Leu984Phe). ESRRA encodes an orphan nuclear receptor regulating steroidogenesis, whereas STARD8 modulates Rho GTPase signaling and cytoskeletal dynamics. Pathway analysis revealed ESRRA enrichment in steroid hormone biosynthesis and oestrogen signaling, whereas STARD8 was enriched in epithelial morphogenesis and cell adhesion pathways. String analysis confirmed ESRRA's predicted transcriptional regulation of STARD8. Both genes showed peak expression during critical urogenital development windows (8-14 weeks).

CONCLUSION

This study suggests a potential ESRRA-STARD8 regulatory pathway contributing to the pathogenesis of concurrent ARM and hypospadias. The convergence of hormonal dysregulation (via ESRRA) and structural defects (via STARD8) provides a unified molecular mechanism for these complex malformations. These findings have immediate implications for genetic screening, counseling, and potentially personalized surgical management of affected children.