{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T03:43:51Z","timestamp":1772768631493,"version":"3.50.1"},"reference-count":18,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Introduction\/background<\/jats:title><jats:p>Bladder exstrophy epispadias complex (BEEC) is a rare congenital anomaly of unknown etiology, although, genetic and environmental factors have been associated with its development. Variants in several genes expressed in the urogenital pathway have been reported as causative for bladder exstrophy in human and murine models. The expansion of next-generation sequencing and molecular genomics has improved our ability to identify the underlying genetic causes of similarly complex diseases and could thus assist with the investigation of the molecular basis of BEEC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>The objective was to identify the presence of rare heterozygous variants in genes previously implicated in bladder exstrophy and correlate them with the presence or absence of bladder regeneration in our study population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p>We present a case series of 12 patients with BEEC who had bladder biopsies performed by pediatric urology during bladder neck reconstruction or bladder augmentation. Cases were classified as \u201csufficient\u201d or \u201cinsufficient\u201d (n = 5 and 7, respectively) based on a bladder volume of greater than or less than 40% of expected bladder size. Control bladder tissue specimens were obtained from patients (n = 6) undergoing biopsies for conditions other than bladder exstrophy. Whole exome sequencing was performed on DNA isolated from the bladder specimens. Based on the hypothesis of <jats:italic>de novo<\/jats:italic> mutations, as well as the potential implications of autosomal dominant conditions with incomplete penetrance, each case was evaluated for autosomal dominant variants in a set of genes previously implicated in BEEC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our review of the literature identified 44 genes that have been implicated in human models of bladder exstrophy. Our whole exome sequencing data analysis identified rare variants in two of these genes among the cases classified as sufficient, and seven variants in five of these genes among the cases classified as insufficient.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified rare variants in seven previously implicated genes in our BEEC specimens. Additional research is needed to further understand the cellular signaling underlying this potentially genetically heterogeneous embryological condition.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2024.1266210","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T05:17:16Z","timestamp":1717564636000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Rare exonic CELSR3 variants identified in Bladder Exstrophy Epispadias Complex"],"prefix":"10.3389","volume":"15","author":[{"given":"Angie C.","family":"Jelin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolai","family":"Sopko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nara","family":"Sobreira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simeon A.","family":"Boyadjiev","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Wohler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Morrill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. Dane","family":"Witmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Michaud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Valle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Gearhart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Dicarlo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.5489\/cuaj.8601","article-title":"Adult patients treated for bladder exstrophy at a young age: what are their current demands?","volume":"18","author":"Bazinet","year":"2024","journal-title":"Can. Urol. Assoc. J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/gim.2016.131","article-title":"Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene","volume":"19","author":"Bekheirnia","year":"2016","journal-title":"Genet. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4783","DOI":"10.1242\/dev.02621","article-title":"DeltaNp63 plays an anti-apoptotic role in ventral bladder development","volume":"133","author":"Cheng","year":"2006","journal-title":"Development"},{"key":"B4","doi-asserted-by":"publisher","first-page":"861","DOI":"10.3892\/ijmm_00000535","article-title":"p63 (TP73L) a key player in embryonic urogenital development with significant dysregulation in human bladder exstrophy tissue","volume":"26","author":"Ching","year":"2010","journal-title":"Int. J. Mol. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"D914","DOI":"10.1093\/nar\/gku935","article-title":"The Comparative Toxicogenomics Database's 10th year anniversary: update 2015","volume":"43","author":"Davis","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"R96","DOI":"10.1186\/gb-2013-14-9-r96","article-title":"An ENU mutagenesis screen identifies novel and known genes involved in epigenetic processes in the mouse","volume":"14","author":"Daxinger","year":"2013","journal-title":"Genome Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"16053","DOI":"10.1523\/JNEUROSCI.4508-10.2010","article-title":"Wnt\/planar cell polarity signaling controls the anterior-posterior organization of monoaminergic axons in the brainstem","volume":"30","author":"Fenstermaker","year":"2010","journal-title":"J. Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"563.e1","DOI":"10.1016\/j.jpurol.2023.04.039","article-title":"Achieving goal capacity for continence surgery: a cumulative event analysis of bladder exstrophy patients","volume":"19","author":"Khandge","year":"2023","journal-title":"J. Pediatr. Urol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: the human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e228","DOI":"10.3324\/haematol.2015.139790","article-title":"Two novel germline DDX41 mutations in a family with inherited myelodysplasia\/acute myeloid leukemia","volume":"101","author":"Li","year":"2016","journal-title":"Haematologica"},{"key":"B11","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/S0140-6736(18)32042-7","article-title":"Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study","volume":"393","author":"Petrovski","year":"2019","journal-title":"Lancet"},{"key":"B12","doi-asserted-by":"publisher","first-page":"3028","DOI":"10.1002\/ajmg.a.62439","article-title":"Exome sequencing of child-parent trios with bladder exstrophy: findings in 26 children","volume":"185","author":"Pitsava","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"B13","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1002\/bdra.23161","article-title":"Candidate gene association study implicates p63 in the etiology of nonsyndromic bladder-exstrophy-epispadias complex","volume":"97","author":"Qi","year":"2013","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"4","DOI":"10.2174\/1389202916666151014221806","article-title":"Genetics of bladder-exstrophy-epispadias complex (BEEC): systematic elucidation of mendelian and multifactorial phenotypes","volume":"17","author":"Reutter","year":"2016","journal-title":"Curr. Genomics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1002\/humu.22769","article-title":"New tools for mendelian disease gene identification: PhenoDB variant analysis module; and GeneMatcher, a web-based tool for linking investigators with an interest in the same gene","volume":"36","author":"Sobreira","year":"2015","journal-title":"Hum. Mutat."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1002\/ajmg.a.62103","article-title":"Common pathogenesis for sirenomelia, OEIS complex, limb-body wall defect, and other malformations of caudal structures","volume":"185","author":"Stevenson","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"B17","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.jpedsurg.2014.10.036","article-title":"Pediatric surgical complications of major genitourinary reconstruction in the exstrophy-epispadias complex","volume":"50","author":"Stewart","year":"2015","journal-title":"J. Pediatr. Surg."},{"key":"B18","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1038\/19539","article-title":"p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development","volume":"398","author":"Yang","year":"1999","journal-title":"Nature"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1266210\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T10:01:48Z","timestamp":1721383308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1266210\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,5]]},"references-count":18,"alternative-id":["10.3389\/fgene.2024.1266210"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2024.1266210","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,5]]},"article-number":"1266210"}}