{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:26:14Z","timestamp":1790799974780,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sidra Medicine, Doha, Qatar","award":["SDR600658"],"award-info":[{"award-number":["SDR600658"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Hypospadias is a common congenital condition in male infants, characterised by incomplete development of the underside of the penile shaft. Genetic factors play a major role in its development. Therefore, studying genetic contributions, especially in familial cases, can enhance our understanding of disease causes and guide targeted interventions. Materials and Methods: Through a structured biobank for hypospadias, we collected blood samples from individuals with familial hypospadias and their relatives. Whole-genome sequencing (WGS) was performed on 27 individuals across seven families to identify potential genetic causes. Bioinformatics analysis, including the GEMINI tool, was used to assess inheritance patterns of single-nucleotide variants (SNVs) within families and identify potential causative SNVs. Results: We identified three likely pathogenic variants in genes not previously associated with hypospadias in EIF2B5, INO80, and ACADVL genes, in three index patients. These variants co-segregated with the condition within the families. Additionally, we detected variants of uncertain significance in hypospadias-related gene families (DNAH12 and LHFP) and in other genes, such as COL6A3, which may cause the phenotype. No potential causative variants were found in two of the seven studied families, indicating the need for further analysis, including the assessment of copy number variants (CNVs). Functional studies will be crucial to establish the role of the identified variants in the development of hypospadias. Conclusions: This study underscores the importance of disease biobanking and genetic analysis in identifying potential underlying causes of congenital conditions, such as hypospadias. The identified variants provide new opportunities for functional research and may enhance our understanding of hypospadias pathophysiology. These findings broaden the genetic landscape of hypospadias and lay the groundwork for functional validation, improved risk assessment, and personalised medicine strategies.<\/jats:p>","DOI":"10.3390\/genes16111340","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T17:51:43Z","timestamp":1762451503000},"page":"1340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic Insights into Familial Hypospadias Identifying Rare Variants and Their Potential Role in Urethral Development"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7446-4762","authenticated-orcid":false,"given":"Kholoud N.","family":"Al-Shafai","sequence":"first","affiliation":[{"name":"Division of Translational Medicine, Research Branch, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9658-2534","authenticated-orcid":false,"given":"Seem","family":"Arar","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine, Research Branch, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7059-8341","authenticated-orcid":false,"given":"Asma","family":"Jamil","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine, Research Branch, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1190-1344","authenticated-orcid":false,"given":"Amina","family":"Azzah","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine, Research Branch, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1269-2238","authenticated-orcid":false,"given":"Maraeh","family":"Mancha","sequence":"additional","affiliation":[{"name":"Urology Division, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4079-0396","authenticated-orcid":false,"given":"Luis R.","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine, Research Branch, Sidra Medicine, Doha P.O. Box 26999, Qatar"},{"name":"Department of Comparative Medicine, School of Medicine, Yale University, New Haven, CT 06510, USA"},{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tariq","family":"Abbas","sequence":"additional","affiliation":[{"name":"Urology Division, Sidra Medicine, Doha P.O. Box 26999, Qatar"},{"name":"Weill Cornel Medicine-Qatar, Cornell University, Doha P.O. Box 24144, Qatar"},{"name":"College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.eururo.2019.06.027","article-title":"Hypospadias Prevalence and Trends in International Birth Defect Surveillance Systems, 1980\u20132010","volume":"76","author":"Yu","year":"2019","journal-title":"Eur. 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