Whole-Exome Sequencing Study of Hypospadias

Authors

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

Publication Date

5-19-2023

Journal

iScience

DOI

10.1016/j.isci.2023.106663

PMID

37168556

PMCID

PMC10165268

PubMedCentral® Posted Date

4-12-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Techniques in genetics, Human Genetics, Developmental biology, Transcriptomics

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.

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