EN
TÜRKÇE
Poster - 188
Genetic Heterogeneity and Developmental Pathway Disruption in Hypospadias with Anorectal Malformations: Evidence from Whole Exome Sequencing
Jyoti Sharma 1, Chandramouli Goswami 1, Prabudh Goel 1, VIshesh Jain 1, Devendra Kumar Yadav 1, Anjan Kumar Dhua 1, Sandeep Agarwala 1, Rahila sardar 2, Dinesh Gupta 3
1 All India Institute of Medical Sciences, New Delhi
2 Vgenomics Pvt .Ltd
3 International Centre for Genetic Engineering and Biotechnology
Background:
Hypospadias and anorectal malformations (ARM) are common congenital anomalies that often co-occur due to shared embryological origins in the caudal mesoderm. However, the underlying genetic mechanisms remain poorly understood, particularly in non-syndromic cases. Recent advances in next-generation sequencing offer an opportunity to explore the genetic architecture of these complex malformations.
Objective:
To identify rare genetic variants associated with the co-occurrence of hypospadias and ARM using whole exome sequencing (WES) and evaluate their involvement in developmental pathways.
Methods:
Whole exome sequencing was performed on six unrelated male patients presenting with both hypospadias and ARM. Variants were filtered based on rarity (MAF < 0.01), predicted pathogenicity, and relevance to known developmental genes. Variants were classified according to ACMG guidelines.
Results:
All six patients harbored heterozygous variants of uncertain significance (VUS) in genes involved in critical developmental pathways. These included genes related to chromatin remodeling (ARID1B, FBXW7), androgen signaling (HSD17B3, DHCR7), Hedgehog/FGF signaling (RAB23, HS6ST1, RET), mitochondrial function (TWNK, ATAD3A), and mesodermal differentiation (TWIST1). Several genes, such as NEB, ARID1B, CHRNG, and RAB23, were implicated in both hypospadias and cryptorchidism, while RET and SRGAP1 were shared between ARM and CAKUT. Each patient displayed a unique combination of variants, suggesting a high degree of genetic heterogeneity. These findings support a possible oligogenic model, wherein multiple interacting variants contribute to the phenotype.
Conclusion:
This study highlights the presence of diverse VUSs across genes involved in tissue patterning, hormonal signaling, and differentiation, suggesting complex multigenic contributions to the co-occurrence of hypospadias and ARM. The overlapping gene associations across related phenotypes further underscore the need for integrated genetic screening and functional validation in developmental anomaly research.