Genetic insights into hypospadias in the Taiwanese population: A whole-exome sequencing study in a single center

Hypospadias is a common congenital urogenital anomaly with a multifactorial etiology. This study aims to identify rare genetic variants associated with hypospadias in a Taiwanese cohort using whole-exome sequencing (WES) and assess their correlation with clinical phenotypes and surgical outcomes.

A cohort of 55 Taiwanese male patients diagnosed with hypospadias, chordee and buried penis was recruited for genetic analysis. Peripheral blood samples were collected, and DNA was extracted for WES using the Illumina NovaSeq 6000 platform. Variant annotation and filtering were performed based on minor allele frequency (MAF <0.05), ACMG classification, and CADD scores (>30). Identified variants were analyzed for genotype-phenotype associations using Fisher's exact test and logistic regression. Hedgehog (Hh) signaling pathway variants were also assessed for potential involvement in disease pathogenesis.

A total of 23 rare variants were identified in 20 patients, affecting genes involved in androgen signaling, genital development, and steroidogenesis. Pathogenic variant s were detected in AR, DNAH11, SRD5A2, ZEB2, and WDR11, while SRD5A2 and POR variants were enriched in severe cases. Variants in WDR11 and HOXA11 were linked to higher surgical complication risks. Hedgehog pathway variants (MGRN1, MEGF8) were found in a subset of patients, implicating developmental signaling in hypospadias.

This study highlights the genetic heterogeneity of hypospadias, chordee and buried penis in Taiwanese patients and its impact on disease severity and surgical outcomes. Future research should explore larger cohorts, functional validation, and gene-environment interactions to improve clinical management.