Whole-exome sequencing study of hypospadias

• DOI: 10.1016/j.isci.2023.106663
• Publication Date: 2023-04-12T16:11:03Z
• Authors: Zhongzhong Chen; Yunping Lei; Richard H. Finnell; Yu Ding; Zhixi Su; Yaping Wang; Hua Xie; Fang Chen
• Keywords: Medical Sciences; Cell Phenomena; Science; Techniques in genetics; Q; Life Sciences; 610; Human Genetics; Article; 3. Good health; Medical Cell Biology; Medical Microbiology; Medical Molecular Biology; Developmental biology; Medical Specialties; Medicine and Health Sciences; and Immunity; Transcriptomics; Biological Phenomena

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 hotspots 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 × 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. Combined with trios data, transcriptomic, and phenotypical and proteomic characterization 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 pathogenesis of hypospadias as well as genetic counseling.