{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:25:29Z","timestamp":1791804329879,"version":"4.3.4"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["DST\/INSPIRE-IF160538"],"award-info":[{"award-number":["DST\/INSPIRE-IF160538"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Reports"],"abstract":"<jats:p>Background: Nonsyndromic cleft lip with or without palate (NSCL\/P) is a multifactorial and common birth malformation caused by genetic and environmental factors, as well as by teratogens. Genome-wide association studies found genetic variations with modulatory effects of NSCL\/P formation in Chinese and Iranian populations. We aimed to identify the susceptibility of single-nucleotide polymorphisms (SNPs) to nonsyndromic cleft lip with or without palate in the Indian population. Material and Methods: The present study was conducted on NSCL\/P cases and controls. Genomic DNA was extracted from peripheral blood and Axiom- Precision Medicine Research Array (PMRA) was performed. The Axiom-PMRA covers 902,527 markers and several thousand novel risk variants. Quality control-passed samples were included for candidate genetic variation identification, gene functional enrichment, and pathway and network analysis. Results: The genome-wide association study identified fourteen novel candidate gene SNPs that showed the most significant association with the risk of NSCL\/P, and eight were predicted to have regulatory sequences. Conclusion: The GWAS study showed novel candidate genetic variations in NSCL\/P formations. These findings contribute to the understanding of genetic predisposition to nonsyndromic cleft lip with or without palate.<\/jats:p>","DOI":"10.3390\/pediatric13040077","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T03:14:29Z","timestamp":1639365269000},"page":"650-657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Identification of Novel Genomic Variations in Susceptibility to Nonsyndromic Cleft Lip and Palate Patients"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2492-813X","authenticated-orcid":false,"given":"Kapil Kumar","family":"Avasthi","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivasan","family":"Muthuswamy","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, National Institute of Technology, Rourkela 769001, Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambreen","family":"Asim","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Burn and Plastic Surgery, Vivekananda Polyclinic and Institute of Medical Sciences, Lucknow 226007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarita","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.molmed.2011.07.007","article-title":"Breakthroughs in the genetics of orofacial clefting","volume":"17","author":"Mangold","year":"2011","journal-title":"Trends Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Gorlin, R.J., Cohen, M.M., and Hennekam, R.C.M. (2001). Syndromes of the Head and Neck, Oxford University Press.","DOI":"10.1093\/oso\/9780195118612.001.0001"},{"key":"ref_3","first-page":"542078","article-title":"Anatomical Variations in Clefts of the Lip with or without Cleft Palate","volume":"2012","author":"Carroll","year":"2012","journal-title":"Plast. Surg. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.4103\/0970-0358.57182","article-title":"Addressing the challenges of cleft lip and palate research in India","volume":"42","author":"Mossey","year":"2009","journal-title":"Indian J. Plast. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1093\/aje\/kwi214","article-title":"Cleft lip and palate versus cleft lip only: Are they distinct defects?","volume":"162","author":"Harville","year":"2005","journal-title":"Am. J. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/EDE.0b013e3182125f9c","article-title":"Risk of oral clefts in twins","volume":"22","author":"Grosen","year":"2011","journal-title":"Epidemiology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1093\/ejo\/26.1.7","article-title":"The complex genetics of cleft lip and palate","volume":"26","author":"Cobourne","year":"2004","journal-title":"Eur. J. Orthod."},{"key":"ref_8","first-page":"1499","article-title":"MSX1 gene in the etiology orofacial deformities","volume":"69","year":"2015","journal-title":"Postepy Hig. Med. Dosw. (Online)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1177\/0022034518811861","article-title":"The Function and Regulatory Network of Pax9 Gene in Palate Development","volume":"98","author":"Li","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1038\/ng.242","article-title":"Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip","volume":"40","author":"Rahimov","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4879","DOI":"10.1093\/hmg\/ddp444","article-title":"FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate","volume":"18","author":"Moreno","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/ng.333","article-title":"Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24","volume":"41","author":"Birnbaum","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/j.jpeds.2009.06.020","article-title":"A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24","volume":"155","author":"Grant","year":"2009","journal-title":"J. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/ng.506","article-title":"Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate","volume":"42","author":"Mangold","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/ng.580","article-title":"A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4","volume":"42","author":"Beaty","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/ng.2360","article-title":"Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci","volume":"44","author":"Ludwig","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s00439-013-1283-6","article-title":"Confirming genes influencing risk to cleft lip with\/without cleft palate in a case-parent trio study","volume":"132","author":"Beaty","year":"2013","journal-title":"Hum Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6414","DOI":"10.1038\/ncomms7414","article-title":"Genome-wide association study identifies a new susceptibility locus for cleft lip with or without a cleft palate","volume":"6","author":"Sun","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ludwig, K.U., Ahmed, S.T., B\u00f6hmer, A.C., Sangani, N.B., Varghese, S., Klamt, J., Schuenke, H., G\u00fcltepe, P., Hofmann, A., and Rubini, M. (2016). Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005914"},{"key":"ref_20","first-page":"2862","article-title":"A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13","volume":"25","author":"Leslie","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"14364","DOI":"10.1038\/ncomms14364","article-title":"Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity","volume":"8","author":"Yu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1111\/cge.13141","article-title":"Common variants in DLG1 locus are associated with non-syndromic cleft lip with or without cleft palate","volume":"93","author":"Mostowska","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_23","first-page":"829","article-title":"Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip \u00b1 cleft palate and cleft palate only","volume":"26","author":"Ludwig","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s00439-016-1754-7","article-title":"Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate","volume":"136","author":"Leslie","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1534\/genetics.114.165225","article-title":"Whole exome sequencing of distant relatives in multiplex families implicates rare variants in candidate genes for oral clefts","volume":"197","author":"Bureau","year":"2014","journal-title":"Genetics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.ajhg.2018.04.009","article-title":"Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate","volume":"102","author":"Cox","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1002\/humu.23793","article-title":"Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans","volume":"40","author":"Cox","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Huang, T., Shu, Y., and Cai, Y.D. (2015). Genetic differences among ethnic groups. BMC Genom., 16.","DOI":"10.1186\/s12864-015-2328-0"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nrg2933","article-title":"Cleft lip and palate: Understanding genetic and environmental influences","volume":"12","author":"Dixon","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1136\/bmj.38106.559120.7C","article-title":"Long term follow up study of survival associated with cleft lip and palate at birth","volume":"328","author":"Christensen","year":"2004","journal-title":"BMJ"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1177\/154405910808700202","article-title":"Unraveling human cleft lip and palate research","volume":"87","author":"Vieira","year":"2008","journal-title":"J. Dent. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kobayashi, G.S., Alvizi, L., Sunaga, D.Y., Francis-West, P., Kuta, A., Almada, B.V.P., Ferreira, S.G., De Andrade-Lima, L.C., Bueno, D.F., and Raposo-Amaral, C.E. (2013). Susceptibility to DNA damage as a molecular mechanism for non-syndromic cleft lip and palate. PLoS ONE., 8.","DOI":"10.1371\/journal.pone.0065677"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1002\/bdra.23275","article-title":"Genetic variants in BRIP1 (BACH1) contribute to risk of nonsyndromic cleft lip with or without cleft palate","volume":"100","author":"Mostowska","year":"2014","journal-title":"Birth. Defects Res. A Clin. Mol. Teratol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1093\/aje\/kwi132","article-title":"Cancer risk in persons with oral cleft\u2014A population-based study of 8,093 cases","volume":"161","author":"Bille","year":"2005","journal-title":"Am. J. Epidemiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Li, A., Qin, G., and Suzuki, A. (2019). Network-based identification of critical regulators as putative drivers of human cleft lip. BMC Med. Genomics., 12.","DOI":"10.1186\/s12920-018-0458-3"}],"container-title":["Pediatric Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2036-7503\/13\/4\/77\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:43:35Z","timestamp":1760168615000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2036-7503\/13\/4\/77"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,8]]},"references-count":36,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["pediatric13040077"],"URL":"https:\/\/doi.org\/10.3390\/pediatric13040077","relation":{},"ISSN":["2036-7503"],"issn-type":[{"value":"2036-7503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,8]]}}}