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Methods: To identify new risk loci, we conducted a genome-wide gene\u2013environment interaction (GEI) analysis of CL\/P with maternal smoking and vitamin use in Filipinos (Ncases = 540, Ncontrols = 260). Since GEI analyses are typically low in power and the results can be difficult to interpret, we applied multiple testing frameworks to evaluate potential GEI effects: a one degree-of-freedom (1df) GxE test, the 3df joint test, and the two-step EDGE approach. Results: While no genome-wide significant interactions were detected, we identified 11 suggestive GEIs with smoking and 24 with vitamin use. Several implicated loci contain biologically plausible genes. Notable interactions with smoking include loci near FEZF1, TWIST2, and NET1. While FEZF1 is involved in early neuronal development, TWIST2 and NET1 regulate epithelial\u2013mesenchymal transition, which is required for proper lip and palate fusion. Interactions with vitamins encompass CECR2\u2014a chromatin remodeling protein required for neural tube closure\u2014and FURIN, a critical protease during early embryogenesis that activates various growth factors and extracellular matrix proteins. The activity of both proteins is influenced by folic acid. Conclusions: Our findings highlight the critical role of maternal exposures in identifying genes associated with structural birth defects such as CL\/P and provide new paths to explore for CL\/P genetics.<\/jats:p>","DOI":"10.3390\/genes16080876","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T11:38:41Z","timestamp":1753443521000},"page":"876","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Gene-by-Environment Interactions Involving Maternal Exposures with Orofacial Cleft Risk in Filipinos"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5349-6562","authenticated-orcid":false,"given":"Zeynep","family":"Erdogan-Yildirim","sequence":"first","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5483-0833","authenticated-orcid":false,"given":"Jenna C.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Biostatistics and Health Data Science, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7117-9536","authenticated-orcid":false,"given":"Nandita","family":"Mukhopadhyay","sequence":"additional","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J.","family":"Leslie-Clarkson","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5812-1871","authenticated-orcid":false,"given":"Carmencita D.","family":"Padilla","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of the Philippines Manila, Ermita, Manila 1000, Metro Manila, Philippines"},{"name":"Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Ermita, Manila 1000, Metro Manila, Philippines"},{"name":"Newborn Screening Reference Center, National Institutes of Health, University of the Philippines Manila, Ermita, Manila 1000, Metro Manila, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey C.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Iowa School of Medicine, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri H.","family":"Beaty","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Bloomberg School of Public Health, John Hopkins University, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9467-4556","authenticated-orcid":false,"given":"Seth M.","family":"Weinberg","sequence":"additional","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2648-2832","authenticated-orcid":false,"given":"Mary L.","family":"Marazita","sequence":"additional","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Departments of Psychiatry and Clinical and Translational Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1897-1131","authenticated-orcid":false,"given":"John R.","family":"Shaffer","sequence":"additional","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"ref_1","first-page":"7","article-title":"Clinical and epidemiologic studies of cleft Lip and palate in the Philippines","volume":"34","author":"Murray","year":"1997","journal-title":"Cleft Palate Craniofacial J."},{"key":"ref_2","first-page":"27","article-title":"Profile of Oral Cleft Cases Reported in the Philippine Oral Cleft Registry from May 2003 to December 2006","volume":"42","author":"Lucero","year":"2008","journal-title":"Acta Med. Philipp."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.gde.2005.03.003","article-title":"Orofacial clefting: Recent insights into a complex trait","volume":"15","author":"Jugessur","year":"2005","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1002\/bdra.20179","article-title":"Plasma zinc concentrations of mothers and the risk of nonsyndromic oral clefts in their children: A case-control study in the Philippines","volume":"73","author":"Tamura","year":"2005","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/bdra.20348","article-title":"Maternal plasma pyridoxal-5\u2032-phosphate concentrations and risk of isolated oral clefts in the Philippines","volume":"79","author":"Tamura","year":"2007","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1002\/bdra.20037","article-title":"Maternal vitamin B-6 and folate status and risk of oral cleft birth defects in the Philippines","volume":"70","author":"Munger","year":"2004","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/bdra.23417","article-title":"Parental risk factors for oral clefts among Central Africans, Southeast Asians, and Central Americans","volume":"103","author":"Figueiredo","year":"2015","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12199-020-00924-y","article-title":"National, regional, and global prevalence of cigarette smoking among women\/females in the general population: A systematic review and meta-analysis","volume":"26","author":"Jafari","year":"2021","journal-title":"Environ. Health Prev. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"020410","DOI":"10.7189\/jogh.10.020410","article-title":"The role of smoke from cooking indoors over an open flame and parental smoking on the risk of cleft lip and palate: A case-control study in 7 low-resource countries","volume":"10","author":"Auslander","year":"2020","journal-title":"J. Glob. Health"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/bs.ctdb.2022.10.006","article-title":"Gene \u00d7 environment associations in orofacial clefting","volume":"152","author":"Marazita","year":"2023","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1055\/s-0041-1722951","article-title":"Genetic Factors in Nonsyndromic Orofacial Clefts","volume":"7","author":"Khan","year":"2020","journal-title":"Glob. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1177\/0022034517720403","article-title":"The role of noncoding genetic variation in isolated orofacial clefts","volume":"96","author":"Thieme","year":"2017","journal-title":"J. Dent. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1093\/aje\/kwi336","article-title":"Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts","volume":"162","author":"Shaw","year":"2005","journal-title":"Am. J. Epidemiol."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1002\/bdra.22885","article-title":"Evidence of gene-environment interaction for the RUNX2 gene and environmental tobacco smoke in controlling the risk of cleft lip with\/without cleft palate","volume":"94","author":"Wu","year":"2012","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Carlson, J.C., Shaffer, J.R., Deleyiannis, F., Hecht, J.T., Wehby, G.L., Christensen, K., Feingold, E., Weinberg, S.M., Marazita, M.L., and Leslie, E.J. (2022). Genome-wide interaction study implicates VGLL2 and alcohol exposure and PRL and smoking in orofacial cleft risk. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.621261"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Haaland, \u00d8.A., Lie, R.T., Romanowska, J., Gjerdevik, M., Gjessing, H.K., and Jugessur, A. (2018). A genome-wide search for gene-environment effects in isolated cleft lip with or without cleft palate triads points to an interaction between maternal periconceptional vitamin use and variants in ESRRG. Front. Genet., 9.","DOI":"10.3389\/fgene.2018.00060"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhang, W., Venkataraghavan, S., Hetmanski, J.B., Leslie, E.J., Marazita, M.L., Feingold, E., Weinberg, S.M., Ruczinski, I., Taub, M.A., and Scott, A.F. (2021). Detecting gene-environment interaction for maternal exposures using case-parent trios ascertained through a case with non-syndromic orofacial cleft. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.621018"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/gepi.20516","article-title":"Quality control and quality assurance in genotypic data for genome-wide association studies","volume":"34","author":"Laurie","year":"2010","journal-title":"Genet. Epidemiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1038\/ng.3656","article-title":"Next-generation genotype imputation service and methods","volume":"48","author":"Das","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1093\/bioinformatics\/btu704","article-title":"minimac2: Faster genotype imputation","volume":"31","author":"Fuchsberger","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Morrison, J. (2023, July 10). BinaryDosage: A Package to Create, Merge, and Read Binary Genotype Files. Version 1.0.0. Available online: https:\/\/cran.rstudio.com\/web\/packages\/BinaryDosage2020.","DOI":"10.32614\/CRAN.package.BinaryDosage"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Morrison, J. (2023, July 10). GxEScanR: Run GWAS\/GWEIS Scans Using Binary Dosage Files [R Package GxEScanR Version 2.0.2]. 2020. Available online: https:\/\/cran.r-project.org\/web\/packages\/GxEScanR.","DOI":"10.32614\/CRAN.package.GxEScanR"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1002\/gepi.21748","article-title":"Finding novel genes by testing G \u00d7 E interactions in a genome-wide association study","volume":"37","author":"Gauderman","year":"2013","journal-title":"Genet. Epidemiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1093\/aje\/kwy278","article-title":"A unified model for the analysis of gene-environment interaction","volume":"188","author":"Gauderman","year":"2019","journal-title":"Am. J. Epidemiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/gepi.20310","article-title":"A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms","volume":"32","author":"Gao","year":"2008","journal-title":"Genet. Epidemiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1093\/bioinformatics\/btq419","article-title":"LocusZoom: Regional visualization of genome-wide association scan results","volume":"26","author":"Pruim","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1016\/j.celrep.2018.03.129","article-title":"High-resolution epigenomic atlas of human embryonic craniofacial development","volume":"23","author":"Wilderman","year":"2018","journal-title":"Cell Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.molcel.2020.03.003","article-title":"Ultrastructural details of mammalian chromosome architecture","volume":"78","author":"Krietenstein","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"The GTEx Consortium (2020). The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science, 369, 1318\u20131330.","DOI":"10.1126\/science.aaz1776"},{"key":"ref_31","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_32","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_33","first-page":"11.10.1","article-title":"From FastQ data to high confidence variant calls: The Genome Analysis Toolkit best practices pipeline","volume":"43","author":"Carneiro","year":"2013","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/s41435-024-00263-w","article-title":"Pivotal role of BCL11B in the immune, hematopoietic and nervous systems: A review of the BCL11B-associated phenotypes from the genetic perspective","volume":"25","author":"Alvarez","year":"2024","journal-title":"Genes. Immun."},{"key":"ref_35","first-page":"bax028","article-title":"GeneHancer: Genome-wide integration of enhancers and target genes in GeneCards","volume":"1","author":"Fishilevich","year":"2017","journal-title":"Database"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"960","DOI":"10.12688\/f1000research.19571.1","article-title":"A genome-wide scan of cleft lip triads identifies parent-of-origin interaction effects between ANK3 and maternal smoking, and between ARHGEF10 and alcohol consumption","volume":"8","author":"Haaland","year":"2019","journal-title":"F1000Research"},{"key":"ref_37","first-page":"469","article-title":"Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate","volume":"35","author":"Beaty","year":"2011","journal-title":"Genet. Epidemiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1086\/510518","article-title":"Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants","volume":"80","author":"Shi","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Wu, T., Schwender, H., Ruczinski, I., Murray, J.C., Marazita, M.L., Munger, R.G., Hetmanski, J.B., Parker, M.M., Wang, P., and Murray, T. (2014). Evidence of gene\u2212environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088088"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1242\/dev.047167","article-title":"Zinc finger genes Fezf1 and Fezf2 control neuronal differentiation by repressing Hes5 expression in the forebrain","volume":"137","author":"Shimizu","year":"2010","journal-title":"Development"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.ajhg.2014.08.006","article-title":"Mutations in FEZF1 cause Kallmann syndrome","volume":"95","author":"Kotan","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Cho, H.J., Shan, Y., Whittington, N.C., and Wray, S. (2019). Nasal placode development, GnRH neuronal migration and Kallmann Syndrome. Front. Cell Dev. Biol., 7.","DOI":"10.3389\/fcell.2019.00121"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Shi, C., Sun, L., and Song, Y. (2019). FEZF1-AS1: A novel vital oncogenic lncRNA in multiple human malignancies. Biosci. Rep., 39.","DOI":"10.1042\/BSR20191202"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13008-023-00101-x","article-title":"Preeclampsia-associated lncRNA FEZF1-AS1 regulates cell proliferation and apoptosis in placental trophoblast cells through the ELAVL1\/NOC2L axis","volume":"18","author":"Zhao","year":"2023","journal-title":"Cell Div."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/s41586-022-05477-4","article-title":"Genetic diversity fuels gene discovery for tobacco and alcohol use","volume":"612","author":"Saunders","year":"2022","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41588-018-0309-3","article-title":"Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences","volume":"51","author":"Biroli","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/s41588-018-0307-5","article-title":"Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use","volume":"51","author":"Liu","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"110821","DOI":"10.1016\/j.celrep.2022.110821","article-title":"Twist2-driven chromatin remodeling governs the postnatal maturation of dermal fibroblasts","volume":"39","author":"Kim","year":"2022","journal-title":"Cell Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ajhg.2015.05.017","article-title":"Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes","volume":"97","author":"Marchegiani","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e206","DOI":"10.1038\/bcj.2014.22","article-title":"The emerging role of Twist proteins in hematopoietic cells and hematological malignancies","volume":"4","author":"Merindol","year":"2014","journal-title":"Blood Cancer J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1002\/ajmg.a.37757","article-title":"Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview","volume":"170","author":"Mazzanti","year":"2016","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4707","DOI":"10.1038\/onc.2011.181","article-title":"Twist2 contributes to breast cancer progression by promoting an epithelial\u2013mesenchymal transition and cancer stem-like cell self-renewal","volume":"30","author":"Fang","year":"2011","journal-title":"Oncogene"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1038\/s41467-023-38526-1","article-title":"Neural crest E-cadherin loss drives cleft lip\/palate by epigenetic modulation via pro-inflammatory gene\u2013environment interaction","volume":"14","author":"Alvizi","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_54","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_55","doi-asserted-by":"crossref","unstructured":"Green, B.L., Fasaye, G.A., Samaranayake, S.G., Duemler, A., Gamble, L.A., and Davis, J.L. (2022). Frequent cleft lip and palate in families with pathogenic germline CDH1 variants. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.1012025"},{"key":"ref_56","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_57","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/1476-4598-12-90","article-title":"Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells","volume":"12","author":"Flowers","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.canlet.2017.04.021","article-title":"RCCD1 depletion attenuates TGF-\u03b2-induced EMT and cell migration by stabilizing cytoskeletal microtubules in NSCLC cells","volume":"400","author":"Wu","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"23815","DOI":"10.1039\/D1RA03299B","article-title":"The interactions of folate with the enzyme furin: A computational study","volume":"11","author":"Sheybani","year":"2021","journal-title":"RSC Adv."},{"key":"ref_60","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_61","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1038\/s41436-021-01216-8","article-title":"Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11","volume":"23","author":"Ravenscroft","year":"2021","journal-title":"Genet. Med."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Dicipulo, R., Norton, K.A., Fairbridge, N.A., Kibalnyk, Y., Fox, S.C., Hornberger, L.K., and McDermid, H.E. (2021). Cecr2 mutant mice as a model for human cat eye syndrome. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-82556-y"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1002\/bdra.20695","article-title":"Cecr2 mutations causing exencephaly trigger misregulation of mesenchymal\/ectodermal transcription factors","volume":"88","author":"Fairbridge","year":"2010","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/bdr2.2146","article-title":"The relationship between maternal periconceptional micronutrient supplementation and non-syndromic cleft lip\/palate in offspring","volume":"115","author":"Liu","year":"2023","journal-title":"Birth Defects Res."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Bai, B., Jiang, Q., Liu, L., Liu, C., and Zhang, Q. (2023). Double whammy: The genetic variants in CECR2 and high Hcy on the development of neural tube defects. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1189847"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"229","DOI":"10.31246\/mjn-2019-0075","article-title":"Prevalence and factors associated with folate deficiency among Filipino women of child-bearing age","volume":"26","author":"Bernardo","year":"2020","journal-title":"Malays. J. 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