{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:47:22Z","timestamp":1790970442511,"version":"4.1.0"},"reference-count":24,"publisher":"SAGE Publications","issue":"10","license":[{"start":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T00:00:00Z","timestamp":1722988800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["K01DE027995"],"award-info":[{"award-number":["K01DE027995"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R37DE08559"],"award-info":[{"award-number":["R37DE08559"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["P50HD103556"],"award-info":[{"award-number":["P50HD103556"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["The Cleft Palate Craniofacial Journal"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Van der Woude Syndrome (VWS) presents with combinations of lip pits (LP) and cleft lip and\/or cleft palate (CL\/P, CPO). VWS phenotypic heterogeneity even amongst relatives, suggests that epigenetic factors may act as modifiers.\n                      <jats:italic>IRF6,<\/jats:italic>\n                      causal for 70% of VWS cases, and\n                      <jats:italic>TP63<\/jats:italic>\n                      interact in a regulatory loop coordinating epithelial proliferation and differentiation in palatogenesis. We hypothesize that differential DNA methylation within\n                      <jats:italic>IRF6<\/jats:italic>\n                      and\n                      <jats:italic>TP63<\/jats:italic>\n                      regulatory regions underlie VWS phenotypic discordance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      DNA methylation of CpG sites in\n                      <jats:italic>IRF6<\/jats:italic>\n                      and\n                      <jats:italic>TP63<\/jats:italic>\n                      promoters and in an\n                      <jats:italic>IRF6<\/jats:italic>\n                      enhancer element was compared amongst blood or saliva DNA samples of 78 unrelated cases. Analyses were done separately for blood and saliva, within each sex and in combination, and to address cleft type (CL\/P\u2009\u00b1\u2009LP vs. CPO\u2009\u00b1\u2009LP) and phenotypic severity (any cleft\u2009+\u2009LP vs. any cleft only).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      For cleft type, blood samples showed higher\n                      <jats:italic>IRF6<\/jats:italic>\n                      and\n                      <jats:italic>TP63<\/jats:italic>\n                      promoter methylation on males with CPO\u2009\u00b1\u2009LP compared to CL\/P\u2009\u00b1\u2009LP and on individuals with CPO\u2009\u00b1\u2009LP compared to those with CL\/P\u2009\u00b1\u2009LP, respectively. Saliva samples showed higher\n                      <jats:italic>IRF6<\/jats:italic>\n                      enhancer methylation on individuals with CPO\u2009\u00b1\u2009LP compared to CL\/P\u2009\u00b1\u2009LP and contrary to above, lower\n                      <jats:italic>TP63<\/jats:italic>\n                      promoter methylation on CPO\u2009\u00b1\u2009LP compared to CL\/P\u2009\u00b1\u2009LP. For phenotypic severity, blood samples showed no differences; however, saliva samples showed higher\n                      <jats:italic>IRF6<\/jats:italic>\n                      promoter methylation in individuals with any cleft\u2009+\u2009LP compared to those without lip pits.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We observed differential methylation in\n                      <jats:italic>IRF6<\/jats:italic>\n                      and\n                      <jats:italic>TP63<\/jats:italic>\n                      regulatory regions associated with cleft type and phenotypic severity, indicating that epigenetic changes in\n                      <jats:italic>IRF6<\/jats:italic>\n                      and\n                      <jats:italic>TP63<\/jats:italic>\n                      can contribute to phenotypic heterogeneity in VWS.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10556656241269495","type":"journal-article","created":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T09:46:13Z","timestamp":1723023973000},"page":"1641-1650","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":7,"title":["DNA Methylation Effects on Van der Woude Syndrome Phenotypic Variability"],"prefix":"10.1177","volume":"62","author":[{"given":"Amanda","family":"Seaberg","sequence":"first","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waheed","family":"Awotoye","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Qian","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ligiane A.","family":"Machado-Paula","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Dunlay","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1229-5964","authenticated-orcid":false,"given":"Azeez","family":"Butali","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"},{"name":"Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Murray","sequence":"additional","affiliation":[{"name":"Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Moreno-Uribe","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2239-8120","authenticated-orcid":false,"given":"Aline L.","family":"Petrin","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2024,8,7]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2012.141"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12675"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1355"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fdmed.2023.1120948"},{"key":"e_1_3_3_6_2","volume-title":"GeneReviews(R)","author":"Schutte BC","year":"1993","unstructured":"Schutte BC, Saal HM, Goudy S, Leslie E. IRF6-Related disorders. . In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). University of Washington, Seattle University of Washington. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved; 1993."},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e318197a49a"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt664"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng985"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.242"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.11.009"},{"key":"e_1_3_3_12_2","first-page":"871460","article-title":"Van der woude syndrome with short review of the literature","volume":"2014","author":"Deshmukh PK","year":"2014","unstructured":"Deshmukh PK, Deshmukh K, Mangalgi A, Patil S, Hugar D, Kodangal SF. Van der woude syndrome with short review of the literature. 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A clinical and multi-omics study of Van der Woude syndrome in three generations of a Chinese family. Mol Med Rep. 2020;22(4):2925-2931. doi:https:\/\/doi.org\/10.3892\/mmr.2020.11365","journal-title":"Mol Med Rep."},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2009.12.007"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1530\/REP-16-0376"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cdev.2021.203674"}],"container-title":["The Cleft Palate Craniofacial Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10556656241269495","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/10556656241269495","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10556656241269495","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T16:21:16Z","timestamp":1777393276000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/10556656241269495"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,7]]},"references-count":24,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1177\/10556656241269495"],"URL":"https:\/\/doi.org\/10.1177\/10556656241269495","relation":{},"ISSN":["1055-6656","1545-1569"],"issn-type":[{"value":"1055-6656","type":"print"},{"value":"1545-1569","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,7]]}}}