{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T20:39:13Z","timestamp":1786653553251,"version":"build-2736575974"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:p>\n                    Hypospadias is a common congenital malformation of the male external genitalia, with severe cases presenting considerable surgical and long-term challenges. Despite the clinical importance of severe hypospadias demonstrated by prolonged hospital stays, repeated surgeries, and substantial costs, the genetic etiology of severe hypospadias remains incompletely understood, particularly in diverse populations. To determine the molecular basis, we performed whole-exome sequencing (WES) on 30 Chinese patients from southeastern China with confirmed 46,XY karyotypes. Our analysis identified clinically relevant genetic variants, including single-nucleotide variants (SNVs) and copy number variations (CNVs), with subsequent phenotypic correlation. Clinically relevant genetic variants were identified in 33.3% (10\/30) of cases, including novel SNVs in gonadal regulators (nuclear receptor subfamily 5 group A member 1 [\n                    <jats:italic toggle=\"yes\">NR5A1<\/jats:italic>\n                    ] c.1344dupC\/c.244+1G&gt;T and SRY-box 3 [\n                    <jats:italic toggle=\"yes\">SOX3<\/jats:italic>\n                    ] c.1273G&gt;C), morphogenetic modulators (GLI family zinc finger 3 [\n                    <jats:italic toggle=\"yes\">GLI3<\/jats:italic>\n                    ] c.4731delA and aristaless-related homeobox [m\n                    <jats:italic toggle=\"yes\">ARX<\/jats:italic>\n                    ] c.644C&gt;G), and syndromic genes (patched domain containing 1 [\n                    <jats:italic toggle=\"yes\">PTCHD1<\/jats:italic>\n                    ] c.667G&gt;A and euchromatic histone lysine methyltransferase 1 [\n                    <jats:italic toggle=\"yes\">EHMT1<\/jats:italic>\n                    ] c.3081C&gt;T). Additionally, recurrent CNVs at 22q12.3 and a novel CNV exon 18 deletion in myelin regulatory factor (\n                    <jats:italic toggle=\"yes\">MYRF<\/jats:italic>\n                    ) and 18q11.2 were identified. Mutation carriers showed a significantly higher frequency of cryptorchidism (40.0%\n                    <jats:italic toggle=\"yes\">vs<\/jats:italic>\n                    5.0%,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    &lt; 0.01) and a higher prevalence of \u22653 associated malformations (80.0%\n                    <jats:italic toggle=\"yes\">vs<\/jats:italic>\n                    35.0%,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    &lt; 0.05) than non-carriers, highlighting genotype\u2013phenotype correlations. The 33.3% diagnostic yield tripled conventional estimates, demonstrating WES efficacy in identifying SNVs and CNVs in severe phenotypes. These findings reveal the genetic heterogeneity of severe hypospadias and support WES utility in uncovering novel variants and structural genomic alterations.\n                  <\/jats:p>","DOI":"10.4103\/aja202583","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T05:00:31Z","timestamp":1770354031000},"page":"276-283","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Identification of gene variants in 30 patients from southeastern China with severe hypospadias by whole-exome sequencing"],"prefix":"10.4103","volume":"28","author":[{"given":"Wen-Hua","family":"Huang","sequence":"first","affiliation":[{"name":"College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China"},{"name":"Department of Urology Surgery, Fujian Children\u2019s Hospital (Fujian Branch of Shanghai Children\u2019s Medical Center Affiliated to Shanghai Jiaotong University School of Medicine), College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian-Qian","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Technology, Puluo (Wuhan) Medical Biotechnology Co., Ltd., Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Urology Surgery, Fujian Children\u2019s Hospital (Fujian Branch of Shanghai Children\u2019s Medical Center Affiliated to Shanghai Jiaotong University School of Medicine), College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Gen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of The Third Surgery, Pinghe County General Hospital, Zhangzhou 363700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Urology Surgery, Fujian Children\u2019s Hospital (Fujian Branch of Shanghai Children\u2019s Medical Center Affiliated to Shanghai Jiaotong University School of Medicine), College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"En-Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Marketing, Wuhan Kindstar Clinical Diagnostic Institute Co., Ltd., Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Technology, Puluo (Wuhan) Medical Biotechnology Co., Ltd., Wuhan 430070, China"},{"name":"Department of Marketing, Wuhan Kindstar Clinical Diagnostic Institute Co., Ltd., Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hao","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Technology, Puluo (Wuhan) Medical Biotechnology Co., Ltd., Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Ming","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China"},{"name":"Department of Urology Surgery, Fujian Children\u2019s Hospital (Fujian Branch of Shanghai Children\u2019s Medical Center Affiliated to Shanghai Jiaotong University School of Medicine), College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"R1-20260430","doi-asserted-by":"crossref","first-page":"57.e1","DOI":"10.1016\/j.jpurol.2021.10.024","article-title":"Anatomical study of hypospadias penis using magnetic resonance imaging in children","volume":"18","author":"Chaudhary","year":"2022","journal-title":"J Pediatr Urol"},{"key":"R2-20260430","doi-asserted-by":"crossref","first-page":"m2070","DOI":"10.1136\/bmj.m2070","article-title":"Hypospadias","volume":"369","author":"Mole","year":"2020","journal-title":"BMJ"},{"key":"R3-20260430","doi-asserted-by":"crossref","first-page":"152.e1","DOI":"10.1016\/j.jpurol.2015.12.002","article-title":"Worldwide prevalence of hypospadias","volume":"12","author":"Springer","year":"2016","journal-title":"J Pediatr Urol"},{"key":"R4-20260430","article-title":"Epidemiology of hypospadias in China:a nationwide surveillance-based study, 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History"}},{"value":"2025-09-28","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}