Whole-exome sequencing study of hypospadias

Hypospadias results from the impaired urethral development, which is influenced by androgens, but its genetic etiology is still unknown. Through whole exome sequencing analysis, we identified NR5A1, SRD5A2, and AR as mutational hot -spots in the etiology of severe hypospadias, as these genes are related to androgen signaling. Additionally, rare damaging variants in cilia-related outer dynein arm heavy chain (ODNAH) genes (DNAH5, DNAH8, DNAH9, DNAH11, and DNAH17) (p = 8.5 3 10(-47)) were significantly enriched in hypospadias cases. The Dnah8 KO mice exhibited significantly decreased testosterone levels, which had an impact on urethral development and disrupted steroid biosynthesis. Com-bined with trios data, transcriptomic, and phenotypical and proteomic character-ization of a mouse model, our work links ciliary genes with hypospadias. Overall, a panel of ODNAH genes with rare damaging variants was identified in 24% of hypospadias patients, providing significant insights into the underlying patho-genesis of hypospadias as well as genetic counseling.