Background: Hypospadias and anorectal malformations (ARM) are common congenital anomalies that frequently co-occur but have poorly understood genetic mechanisms. Both conditions arise from caudal mesodermal derivatives during early embryogenesis. The mTORC2 signaling pathway, in which RICTOR is a critical component, plays essential roles in cell survival, cytoskeletal organization, and epithelial remodeling processes necessary for urethral and cloacal development.
Objective: To identify functionally relevant genetic variants contributing to the co-occurrence of hypospadias and ARM using whole exome sequencing (WES).
Methods: WES was performed on six unrelated male patients presenting with both hypospadias and ARM. Variants were prioritized based on population frequency, predicted pathogenicity, and relevance to urogenital development.
Results: We identified a heterozygous missense variant in RICTOR (NM_152756.5: c.5084C>T; p.Thr1695Ile) in four of six patients (67%). All four patients with the RICTOR variant presented with proximal hypospadias (Types II-III) and severe ARM (imperforate anus or rectourethral fistula). The two patients without the RICTOR variant both carried a missense variant in MMP17 (NM_016155.7: c.C386G; p.A129G), a downstream target of the mTORC2-AKT pathway, along with distinct variants in SOX30, a testis-specific transcription factor. This pattern suggests genetic convergence where disruption at different levels of the mTORC2-AKT signaling cascade contributes to defective mesodermal patterning and urogenital morphogenesis.
Conclusion: This study identifies recurrent variants in RICTOR, MMP17, and SOX30 among patients with coexisting hypospadias and ARM, implicating the mTORC2-AKT signaling pathway as a shared developmental mechanism. These findings support including these genes in diagnostic panels and highlight the need for functional validation studies to confirm their roles in genitourinary and hindgut development.
Keywords: Hypospadias, Anorectal Malformation, RICTOR, MMP17, SOX30, mTORC2, AKT pathway, Whole Exome Sequencing, Cloacal Development
Anahtar Kelimeler: