Evidence map›Paper›PMID 42584835›Full record

ArticleScience China. Life sciences2026

The genetic landscape of hypospadias: clinical insights into inherited and de novo risk factors.

Yanqin You, Yingliu Luo, Honghui Zhou, Qiaowei Liang, Jingjie Xue, Zhuo Li, Yaowang Zhao, Tianqu He, Kexin Wang, Hongyan Wang and 2 more

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Article in Science China. Life sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0cells of the map it votes in
0citing papers in PubMed
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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Yanqin You *Senior Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing, 100853, China.
Yingliu Luo *Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, 410000, China.
Honghui Zhou *Medical Innovation Research Division of Chinese PLA General Hospital, Beijing, 100853, China.
Qiaowei Liang *Department of Medical Genetics, Hunan Jiahui Genetics Hospital, Changsha, 410078, China.
Jingjie XueChina Foundation for Birth Defects, Beijing, 100089, China.
Zhuo LiCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, 410000, China.
Yaowang ZhaoDepartment of Urology, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University, Hunan Children's Hospital, Changsha, 410007, China.
Tianqu HeDepartment of Urology, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University, Hunan Children's Hospital, Changsha, 410007, China.
Kexin WangChina Foundation for Birth Defects, Beijing, 100089, China.
Hongyan WangObstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China.
Zhongzhong ChenGuangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. zhongzhongchen@gmail.com.
Lingqian WuCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, 410000, China. wulingqian@sklmg.edu.cn.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Hypospadias is one of the most common birth defects in China and a key feature of differences in sex development (DSD), yet its genetic etiology remains largely unresolved. Current diagnostic approaches using DSD-targeted gene panels have a low rate of definitive diagnoses (5.5%), highlighting the need for more comprehensive genetic investigation. In this study, we performed next-generation sequencing (NGS) on the largest trio-based cohort of hypospadias to date, comprising 106 pediatric cases and their parents (92 trios). We achieved a definitive genetic diagnosis in 6.6% of patients, identifying pathogenic variants in canonical DSD genes such as AR, NR5A1 and WT1. By incorporating a broader spectrum of potentially clinically significant variants, we increased the overall genetic identification rate to 33.0% (35/106). Strikingly, trio analysis uncovered a significant burden of de novo loss-of-function (LoF) variants (2.2-fold enrichment, P=0.001), primarily driven by variants in genes associated with ciliopathies (10.35-fold, P=0.016), a previously underappreciated gene class in hypospadias. Furthermore, we identified and functionally validated two high-confidence risk genes, PRKCZ and HRNR, based on recurrent de novo variants. Functional assays confirmed that these variants disrupt key biological mechanisms, including cell proliferation, migration, and androgen signaling. Our large-scale trio approach substantially expands the genetic landscape of hypospadias, demonstrates the critical value of trio-based sequencing for improving diagnostic yield, and decisively implicates ciliary genes in its pathogenesis.

Indexed as

ciliopathyde novogeneticshypospadiastrioswhole-exome sequencingwhole-genome sequencing

Identifiers

PMID42584835

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.