Whole-exome sequencing study of hypospadias

Zhongzhong Chen; Yunping Lei; Richard H Finnell; Yu Ding; Zhixi Su; Yaping Wang; Hua Xie; Fang Chen

doi:10.1016/j.isci.2023.106663

Whole-exome sequencing study of hypospadias

iScience. 2023 Apr 12;26(5):106663. doi: 10.1016/j.isci.2023.106663. eCollection 2023 May 19.

Authors

Zhongzhong Chen^{1

2}, Yunping Lei³, Richard H Finnell^{3

4}, Yu Ding¹, Zhixi Su⁵, Yaping Wang¹, Hua Xie¹, Fang Chen^{1

6}

Affiliations

¹ Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China.
² Urogenital Development Research Center, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200062, China.
³ Center for Precision Environmental Health, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Departments of Molecular and Human Genetics and Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ School of Life Sciences, Fudan University, Shanghai 200438, China.
⁶ Clinical Research Center For Hypospadias Pediatric College, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, China.

Abstract

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.

Keywords: Developmental biology; Human Genetics; Techniques in genetics; Transcriptomics.

Grants and funding

P30 ES030285/ES/NIEHS NIH HHS/United States