{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T01:37:21Z","timestamp":1790473041336,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T00:00:00Z","timestamp":1649721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hypospadias is a common form of congenital atypical sex development that is often associated with other congenital comorbidities. Many genes have been associated with the condition, most commonly single sequence variations. Further investigations of recurrent and overlapping copy number variations (CNVs) have resulted in the identification of genes and chromosome regions associated with various conditions, including differences of sex development (DSD). In this retrospective study, we investigated the DECIPHER database, as well as an internal institutional database, to identify small recurrent CNVs among individuals with isolated and syndromic hypospadias. We further investigated these overlapping recurrent CNVs to identify 75 smallest regions of overlap (SROs) on 18 chromosomes. Some of the genes within these SROs may be considered potential candidate genes for the etiology of hypospadias and, occasionally, additional comorbid phenotypes. This study also investigates for the first time additional common phenotypes among individuals with hypospadias and overlapping CNVs. This study provides data that may aid genetic counseling and management of individuals with hypospadias, as well as improve understanding of its underlying genetic etiology and human genital development overall.<\/jats:p>","DOI":"10.3390\/ijms23084246","type":"journal-article","created":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T21:15:35Z","timestamp":1649798135000},"page":"4246","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification of Small Regions of Overlap from Copy Number Variable Regions in Patients with Hypospadias"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3664-2067","authenticated-orcid":false,"given":"Carter H.","family":"Scott","sequence":"first","affiliation":[{"name":"Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina E.","family":"Amarillo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.5958\/j.2322-0422.1.1.012","article-title":"Hypospadias Risk among North-Indian Children","volume":"1","author":"Samtani","year":"2014","journal-title":"Ann. Health Health Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1093\/humupd\/dms002","article-title":"Aetiology of Hypospadias: A Systematic Review of Genes and Environment","volume":"18","author":"Feitz","year":"2012","journal-title":"Hum. Reprod. Update"},{"key":"ref_3","first-page":"754","article-title":"Hypospadias in Istanbul: Incidence and Risk Factors","volume":"53","author":"Akin","year":"2011","journal-title":"Pediatr. Int. Off. J. Jpn. Pediatr. Soc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1159\/000441988","article-title":"The Genetic and Environmental Factors Underlying Hypospadias","volume":"9","author":"Bouty","year":"2015","journal-title":"Sex. Dev."},{"key":"ref_5","unstructured":"Bhat, A. (2022). Hypospadias Embryology, Etiology, and Classification. Hypospadiology, Springer."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00439-002-0799-y","article-title":"Complex Segregation Analysis of Hypospadias","volume":"111","author":"Fredell","year":"2002","journal-title":"Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1097\/MED.0000000000000063","article-title":"Genetic and Environmental Origins of Hypospadias","volume":"21","author":"Thorup","year":"2014","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.juro.2018.04.072","article-title":"Family History Is Underestimated in Children with Isolated Hypospadias: A French Multicenter Report of 88 Families","volume":"200","author":"Ollivier","year":"2018","journal-title":"J. Urol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/aje\/kwm317","article-title":"Familial Aggregation of Hypospadias: A Cohort Study","volume":"167","author":"Schnack","year":"2008","journal-title":"Am. J. Epidemiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6003","DOI":"10.1093\/hmg\/ddv313","article-title":"A New Variant in Signal Peptide of the Human Luteinizing Hormone Receptor (LHCGR) Affects Receptor Biogenesis Causing Leydig Cell Hypoplasia","volume":"24","author":"Vezzoli","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_11","unstructured":"(2020, July 02). [OMIM] Online Mendelian Inheritance in Man Hypospadias Gene Map. Available online: https:\/\/omim.org\/search?index=geneMap&start=1&sort=chromosome_number+asc%2C+chromosome_sort+asc&search=hypospadias&limit=100."},{"key":"ref_12","unstructured":"Human Protein Atlas (2020, July 02). Assays & Annotation. Available online: https:\/\/www.proteinatlas.org\/about\/assays+annotation."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1016\/j.juro.2013.05.061","article-title":"Hypospadias and Genes Related to Genital Tubercle and Early Urethral Development","volume":"190","author":"Carmichael","year":"2013","journal-title":"J. Urol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1007\/s00383-018-4330-5","article-title":"Single-Nucleotide and Copy-Number Variance Related to Severity of Hypospadias","volume":"34","author":"Singh","year":"2018","journal-title":"Pediatr. Surg. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1002\/mgg3.322","article-title":"A Novel Splice Site Variant in CYP11A1 in Trans with the p.E314K Variant in a Male Patient with Congenital Adrenal Insufficiency","volume":"5","author":"Blackburn","year":"2017","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1055\/s-0039-1693151","article-title":"Novel Missense Variants in ADAT3 as a Cause of Syndromic Intellectual Disability","volume":"8","author":"Thomas","year":"2019","journal-title":"J. Pediatr. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"White, J., O\u2019Neill, M., Sheth, K., and Lamb, D. (2020). Murine RBFOX-2 Haploinsufficiency Parallels Congenital Anomalies in Human Patients with RBFOX-2 Copy Number Variants. J. Urol., 203.","DOI":"10.1097\/JU.0000000000000940.11"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1111\/j.1651-2227.2010.01683.x","article-title":"13q33.2 Deletion: A Rare Cause of Ambiguous Genitalia in a Male Newborn with Growth Restriction","volume":"99","author":"Andresen","year":"2010","journal-title":"Acta Paediatr."},{"key":"ref_19","first-page":"673","article-title":"Etiology of Hypospadias: A Comparative Review of Genetic Factors and Developmental Processes between Human and Animal Models","volume":"12","author":"Chang","year":"2020","journal-title":"Res. Rep. Urol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5319","DOI":"10.1038\/s41467-018-07784-9","article-title":"Human Sex Reversal Is Caused by Duplication or Deletion of Core Enhancers Upstream of SOX9","volume":"9","author":"Croft","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/humrep\/deu364","article-title":"Molecular Basis of Non-Syndromic Hypospadias: Systematic Mutation Screening and Genome-Wide Copy-Number Analysis of 62 Patients","volume":"30","author":"Kon","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ajhg.2009.03.010","article-title":"DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources","volume":"84","author":"Firth","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1002\/ajmg.a.37351","article-title":"Recurrent Duplications of 17q12 Associated with Variable Phenotypes","volume":"167","author":"Mitchell","year":"2015","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1097\/01.ju.0000138343.20069.5f","article-title":"Genome-Wide Linkage Analysis for Hypospadias Susceptibility Genes","volume":"172","author":"Luthman","year":"2004","journal-title":"J. Urol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00439-008-0533-5","article-title":"A New Susceptibility Locus for Hypospadias on Chromosome 7q32.2-Q36.1","volume":"124","author":"Thai","year":"2008","journal-title":"Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tannour-Louet, M., Han, S., Corbett, S.T., Louet, J.-F., Yatsenko, S., Meyers, L., Shaw, C.A., Kang, S.-H.L., Cheung, S.W., and Lamb, D.J. (2010). Identification of de Novo Copy Number Variants Associated with Human Disorders of Sexual Development. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015392"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1056\/NEJMsr1406261","article-title":"ClinGen\u2014The Clinical Genome Resource","volume":"372","author":"Rehm","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of Protein-Coding Genetic Variation in 60,706 Humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"ref_29","unstructured":"McKusick-Nathans Institute of Genetic Medicine (2020). Online Mendelian Inheritance in Man, OMIM\u00ae, Johns Hopkins University."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1530\/EC-18-0022","article-title":"Disorders of Sex Development: A Study of 194 Cases","volume":"7","author":"Walia","year":"2018","journal-title":"Endocr. Connect."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S491","DOI":"10.1542\/peds.2017-0230","article-title":"Proximal Hypospadias and a Novel WT1 Variant: When Should Genetic Testing Be Considered?","volume":"141","author":"Dabrowski","year":"2018","journal-title":"Pediatrics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1097\/JU.0000000000000810","article-title":"Proximal Hypospadias: Isolated Genital Condition or Marker of More?","volume":"204","author":"Johnson","year":"2020","journal-title":"J. Urol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16012","DOI":"10.1038\/hgv.2016.12","article-title":"Integrated Small Copy Number Variations and Epigenome Maps of Disorders of Sex Development","volume":"3","author":"Amarillo","year":"2016","journal-title":"Hum. Genome Var."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1038\/nrg3871","article-title":"A Copy Number Variation Map of the Human Genome","volume":"16","author":"Zarrei","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/gim.2014.178","article-title":"A High-Resolution Copy-Number Variation Resource for Clinical and Population Genetics","volume":"17","author":"Uddin","year":"2015","journal-title":"Genet. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1093\/jalm\/jfaa165","article-title":"Creating Affirmative and Inclusive Practices When Providing Genetic and Genomic Diagnostic and Research Services to Gender-Expansive and Transgender Patients","volume":"6","author":"Theisen","year":"2020","journal-title":"J. Appl. Lab. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1136\/jmg.8.2.153","article-title":"v Genetic Studies on Hypospadias in Males","volume":"8","author":"Chen","year":"1971","journal-title":"J. Med. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0015-0282(00)00629-4","article-title":"Absence of Y-Chromosome Microdeletions in Patients with Isolated Hypospadias","volume":"74","author":"Tateno","year":"2000","journal-title":"Fertil. Steril."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1159\/000444938","article-title":"Copy Number Variations of the Azoospermia Factor Region and SRY Are Not Associated with the Risk of Hypospadias","volume":"10","author":"Kon","year":"2016","journal-title":"Sex. Dev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"OR02-01","DOI":"10.1210\/jendso\/bvaa046.037","article-title":"Gene Dosage Changes in RBFOX-2 Can Affect Upper and Lower Tract Genitourinary Development","volume":"4","author":"White","year":"2020","journal-title":"J. Endocr. Soc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"W214","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA Prediction Server: Biological Network Integration for Gene Prioritization and Predicting Gene Function","volume":"38","author":"Donaldson","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Jamsheer, A., Sowi\u0144ska, A., Simon, D., Jamsheer-Bratkowska, M., Trzeciak, T., and Latos-Biele\u0144ska, A. (2013). Bilateral Radial Agenesis with Absent Thumbs, Complex Heart Defect, Short Stature, and Facial Dysmorphism in a Patient with Pure Distal Microduplication of 5q35.2\u20135q35.3. BMC Med. Genet., 14.","DOI":"10.1186\/1471-2350-14-13"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rafi, S.K., and Butler, M.G. (2020). The 15q11.2 BP1-BP2 Microdeletion (Burnside\u2013Butler) Syndrome: In Silico Analyses of the Four Coding Genes Reveal Functional Associations with Neurodevelopmental Disorders. Int. J. Mol. Sci., 21.","DOI":"10.37247\/PAMOLSCS.1.2020.17"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/jcpp.12290","article-title":"Hypospadias and Increased Risk for Neurodevelopmental Disorders","volume":"56","author":"Butwicka","year":"2015","journal-title":"J. Child Psychol. Psychiatry Allied Discip."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/MCD.0000000000000275","article-title":"DDD Study Cardiac Disorders and Structural Brain Abnormalities Are Commonly Associated with Hypospadias in Children with Neurodevelopmental Disorders","volume":"28","author":"Gazdagh","year":"2019","journal-title":"Clin. Dysmorphol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.ejmg.2013.06.008","article-title":"Loss-of-Function Variation in the DPP6 Gene Is Associated with Autosomal Dominant Microcephaly and Mental Retardation","volume":"56","author":"Liao","year":"2013","journal-title":"Eur. J. Med. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.mod.2016.05.004","article-title":"Requirement for Basement Membrane Laminin A5 during Urethral and External Genital Development","volume":"141","author":"Lin","year":"2016","journal-title":"Mech. Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.eururo.2020.12.036","article-title":"How Far Should We Explore Hypospadias? Next-Generation Sequencing Applied to a Large Cohort of Hypospadiac Patients","volume":"79","author":"Ea","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1136\/jmedgenet-2019-106354","article-title":"Under-Reported Aspects of Diagnosis and Treatment Addressed in the Dutch-Flemish Guideline for Comprehensive Diagnostics in Disorders\/Differences of Sex Development","volume":"57","author":"Wolffenbuttel","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Huang, N., Lee, I., Marcotte, E.M., and Hurles, M.E. (2010). Characterising and Predicting Haploinsufficiency in the Human Genome. PLoS Genet., 6.","DOI":"10.1371\/journal.pgen.1001154"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Haraksingh, R.R., Abyzov, A., Gerstein, M., Urban, A.E., and Snyder, M. (2011). Genome-Wide Mapping of Copy Number Variation in Humans: Comparative Analysis of High Resolution Array Platforms. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027859"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1038\/ng.3063","article-title":"Genome-Wide Association Analyses Identify Variants in Developmental Genes Associated with Hypospadias","volume":"46","author":"Geller","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/ng.721","article-title":"Common Variants in DGKK Are Strongly Associated with Risk of Hypospadias","volume":"43","author":"Feitz","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jsbmb.2016.10.009","article-title":"Altered SOX9 Genital Tubercle Enhancer Region in Hypospadias","volume":"170","author":"Sreenivasan","year":"2017","journal-title":"J. Steroid Biochem. Mol. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/8\/4246\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:52:21Z","timestamp":1760136741000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/8\/4246"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,12]]},"references-count":54,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ijms23084246"],"URL":"https:\/\/doi.org\/10.3390\/ijms23084246","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,12]]}}}