{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T01:39:17Z","timestamp":1783820357354,"version":"3.55.0"},"reference-count":39,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T00:00:00Z","timestamp":1668556800000},"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":["DE28300"],"award-info":[{"award-number":["DE28300"]}],"id":[{"id":"10.13039\/100000072","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":[[2024,4]]},"abstract":"\n \n Objectives<\/jats:italic>\n <\/jats:title>\n Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL\u2009\u00b1\u2009P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL\u2009\u00b1\u2009P in our cohorts.<\/jats:p>\n <\/jats:sec>\n \n \n Materials and Methods:<\/jats:italic>\n <\/jats:title>\n We conducted next-generation sequencing (NGS) analysis of 130 nsCL\u2009\u00b1\u2009P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL\u2009\u00b1\u2009P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL\u2009\u00b1\u2009P.<\/jats:p>\n <\/jats:sec>\n \n \n Results<\/jats:italic>\n <\/jats:title>\n \n We discovered damaging mutations within the\n AFDN<\/jats:italic>\n gene, a cell adhesion molecule (CAMs) that was previously shown to contribute to cleft palate in mice. These mutations include p.Met1164Ile, p.Thr453Asn, p.Pro1638Ala, p.Arg669Gln, p.Ala1717Val, and p.Arg1596His. We also discovered a novel splicing p.Leu1588Leu mutation in this protein. Computational analysis suggests that these amino acid changes affect the interactions with other cleft-associated genes including nectins (PVRL1, PVRL2, PVRL3, and PVRL4) CDH1, CTNNA1, and CTNND1.\n <\/jats:p>\n <\/jats:sec>\n \n \n Conclusion<\/jats:italic>\n <\/jats:title>\n \n This is the first report on the contribution of\n AFDN<\/jats:italic>\n to the risk for nsCL\u2009\u00b1\u2009P in humans.\n AFDN<\/jats:italic>\n encodes AFADIN, an important CAM that forms calcium-independent complexes with nectins 1 and 4 (encoded by the genes\n PVRL1<\/jats:italic>\n and\n PVRL4<\/jats:italic>\n ). This discovery shows the power of NGS analysis of multiethnic cleft samples in combination with a computational approach in the understanding of the pathogenesis of nsCL\u2009\u00b1\u2009P.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1177\/10556656221135926","type":"journal-article","created":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T02:10:32Z","timestamp":1668651032000},"page":"697-705","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":7,"title":["Damaging Mutations in\n \n AFDN<\/i>\n <\/b>\n Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate"],"prefix":"10.1177","volume":"61","author":[{"given":"Waheed","family":"Awotoye","sequence":"first","affiliation":[{"name":"Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA, USA"},{"name":"Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A","family":"Mossey","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, University of Dundee, Dundee, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline B","family":"Hetmanski","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0080-9101","authenticated-orcid":false,"given":"Lord J J","family":"Gowans","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6164-4083","authenticated-orcid":false,"given":"Mekonen 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Cleft lip and palate genetics and application in early embryological development. Indian J Plast Surg. 2009;42(Suppl):S35-S50.","journal-title":"Indian J Plast Surg"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.3390\/biology11020153"},{"key":"e_1_3_2_22_2","first-page":"229","article-title":"Multidisciplinary approach to genomics research in Africa: the AfriCRAN model","volume":"21","author":"Butali A","year":"2015","unstructured":"Butali A, Mossey P, Tiffin N, et al. Multidisciplinary approach to genomics research in Africa: the AfriCRAN model. Pan Afr Med J. 2015;21:229.","journal-title":"Pan Afr Med J"},{"key":"e_1_3_2_23_2","doi-asserted-by":"crossref","unstructured":"Awotoye W Mossey P Hetmanski J et al. Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip\/Palate. 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