EN
TÜRKÇE
Oral Presentation - 25
mTORC2 Pathway Disruption in the Dual Occurrence of Hypospadias and Anorectal Malformations: Evidence from WES
Chandramouli Goswami 1, Prabudh Goel 1, Jyoti Sharma 1, Sourabh Kumar 1, VIshesh Jain 1, Anjan Kumar Dhua 1, Devendra Kumar Yadav 1, Masarrat Afroz 2, Vikas Dhikav 2, Harpreet Singh 3, Rahila Salman 4, Dinesh Gupta 5
1 All India Institute of Medical Sciences, New Delhi
2 Department of Health Research, Ministry of Health & Family Welfare, Goverment of India
3 Indian Council of Medical Research
4 Vgenomics
5 International Centre for Genetic Engineering and Biotechnology
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.