Whole-exome sequencing study of hypospadias

被引：10

作者：

Chen, Zhongzhong ^{[1
,2
]}

Lei, Yunping ^{[3
]}

Finnell, Richard H. ^{[3
,4
,5
]}

Ding, Yu ^{[1
]}

Su, Zhixi ^{[6
]}

Wang, Yaping ^{[1
]}

Xie, Hua ^{[1
]}

Chen, Fang ^{[1
,7
]}

机构：

[1] Shanghai Jiao Tong Univ, Shanghai Childrens Hosp, Sch Med, Dept Urol, Shanghai 200062, Peoples R China

[2] Shanghai Jiao Tong Univ, Shanghai Childrens Hosp, Urogenital Dev Res Ctr, Sch Med, Shanghai 200062, Peoples R China

[3] Baylor Coll Med, Ctr Precis Environm Hlth, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[6] Fudan Univ, Sch Life Sci, Shanghai 200438, Peoples R China

[7] Shanghai Jiao Tong Univ, Sch Med, Clin Res Ctr Hypospadias Pediat Coll, Shanghai 200062, Peoples R China

来源：

ISCIENCE | 2023年 / 26卷 / 05期

基金：

中国国家自然科学基金;

关键词：

VARIANTS; ASSOCIATION; MUTATIONS; TRAITS;

D O I：

10.1016/j.isci.2023.106663

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：21

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