{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T03:47:51Z","timestamp":1776916071505,"version":"3.51.2"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T00:00:00Z","timestamp":1660694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Rs560426 at 1p22 was proved to be associated with NSCL\/P (non-syndromic cleft lip with or without the palate) in several populations, including Han Chinese population. Here, we conducted a deep sequencing around rs560426 to locate more susceptibility variants in this region. In total, 2,293 NSCL\/P cases and 3,235 normal controls were recruited. After sequencing, association analysis was performed. Western blot, RT-qPCR, HE, immunofluorescence staining, and RNA sequencing were conducted for functional analyses of the selected variants. Association analysis indicated that rs77179923 was the only SNP associated with NSCLP specifically (<jats:italic>p<\/jats:italic> = 4.70E-04, OR = 1.84), and rs12071152 was uniquely associated with LCLO (<jats:italic>p<\/jats:italic> = 4.00E-04, OR = 1.30, 95%CI: 1.12\u20131.51). Moreover, <jats:italic>de novo<\/jats:italic> harmful rare variant NM_004815.3, NP_004806.3; c.1652G&amp;gt;C, p.R551T in <jats:italic>ARHGAP29<\/jats:italic> resulted in a decreased expression level of <jats:italic>ARHGAP29<\/jats:italic>, which in turn affected NSCL\/P-related biological processes; however, no overt cleft palate (CP) phenotype was observed. In conclusion, rs12071152 was a new susceptible variant, which is specifically associated with LCLO among the Han Chinese population. Allele A of it could increase the risk of having a cleft baby. Rs77179923 and rare variant NM_004815.3, NP_004806.3; c.1652G&amp;gt;C, p.R551T at 1p22 were both associated with NSCLP among the Han Chinese population. However, this missense variation contributes to no overt CP phenotype due to dosage insufficiency or compensation from other genes.<\/jats:p>","DOI":"10.3389\/fgene.2022.947126","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T04:33:58Z","timestamp":1660710838000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeted re-sequencing on 1p22 among non-syndromic orofacial clefts from Han Chinese population"],"prefix":"10.3389","volume":"13","author":[{"given":"Mu-Jia","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-Yu","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bi-He","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian-Ming","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong-Lin","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"Unit7.20","DOI":"10.1002\/0471142905.hg0720s76","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2","volume":"7","author":"Adzhubei","year":"2013","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1126\/science.1156409","article-title":"Genetic mapping in human disease","volume":"322","author":"Altshuler","year":"2008","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.19191\/ep18.3-4.S1.P001.057","article-title":"Environmental and individual exposure and the risk of congenital anomalies: a review of recent epidemiological evidence","volume":"42","author":"Baldacci","year":"2018","journal-title":"Epidemiol. Prev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2800","DOI":"10.12688\/f1000research.9503.1","article-title":"Genetic factors influencing risk to orofacial clefts: today's challenges and tomorrow's opportunities","volume":"5","author":"Beaty","year":"2016","journal-title":"F1000Res"},{"key":"B5","doi-asserted-by":"publisher","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":"B6","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1038\/ng.f.136","article-title":"Common and rare variants in multifactorial susceptibility to common diseases","volume":"40","author":"Bodmer","year":"2008","journal-title":"Nat. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2567","DOI":"10.1002\/ajmg.a.36691","article-title":"Rare functional variants in genome-wide association identified candidate genes for nonsyndromic clefts in the African population","author":"Butali","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1002\/bdr2.23605","article-title":"Identifying genetic sources of phenotypic heterogeneity in orofacial clefts by targeted sequencing","volume":"109","author":"Carlson","year":"2017","journal-title":"Birth Defects Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"528","DOI":"10.4103\/1305-7456.143637","article-title":"Identification of a novel heterozygous truncation mutation in exon 1 of ARHGAP29 in an Indian subject with nonsyndromic cleft lip with cleft palate","volume":"8","author":"Chandrasekharan","year":"2014","journal-title":"Eur. J. Dent."},{"key":"B10","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1002\/(sici)1096-8628(19980827)79:1<42::aid-ajmg11>3.0.co;2-m","article-title":"Racial and ethnic variations in the prevalence of orofacial clefts in California, 1983-1992","volume":"79","author":"Croen","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2156","DOI":"10.1093\/bioinformatics\/btr330","article-title":"The variant call format and VCFtools","volume":"27","author":"Danecek","year":"2011","journal-title":"Bioinformatics"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e1000294","DOI":"10.1371\/journal.pbio.1000294","article-title":"Rare variants create synthetic genome-wide associations","volume":"8","author":"Dickson","year":"2010","journal-title":"PLoS Biol."},{"key":"B13","doi-asserted-by":"publisher","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":"B14","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1177\/0022034516657003","article-title":"Association studies and direct DNA sequencing implicate genetic susceptibility loci in the etiology of nonsyndromic orofacial clefts in sub-saharan african populations","volume":"95","author":"Gowans","year":"2016","journal-title":"J. Dent. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1136\/jmg.2009.069385","article-title":"A cohort study of recurrence patterns among more than 54, 000 relatives of oral cleft cases in denmark: support for the multifactorial threshold model of inheritance","volume":"47","author":"Grosen","year":"2010","journal-title":"J. Med. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e1008357","DOI":"10.1371\/journal.pgen.1008357","article-title":"Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft","volume":"15","author":"Huang","year":"2019","journal-title":"PLoS Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60, 706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1002\/bdra.23076","article-title":"Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome-wide association on chromosome 1p22","volume":"94","author":"Leslie","year":"2012","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1002\/ajmg.c.31381","article-title":"Genetics of cleft lip and cleft palate","author":"Leslie","year":"2013","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"B21","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.ajhg.2015.01.004","article-title":"Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci","volume":"96","author":"Leslie","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1002\/bdra.23286","article-title":"Further evidence suggesting a role for variation in ARHGAP29 variants in nonsyndromic cleft lip\/palate","volume":"100","author":"Letra","year":"2014","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e20170628","DOI":"10.1542\/peds.2017-0628","article-title":"The primary care pediatrician and the care of children with cleft lip and\/or cleft palate","volume":"139","author":"Lewis","year":"2017","journal-title":"Pediatrics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with burrows-wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"B26","doi-asserted-by":"publisher","first-page":"eaaw0946","DOI":"10.1126\/sciadv.aaw0946","article-title":"p63 establishes epithelial enhancers at critical craniofacial development genes","volume":"5","author":"Lin-Shiao","year":"2019","journal-title":"Sci. Adv."},{"key":"B27","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1002\/bdra.23596","article-title":"Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate","volume":"109","author":"Liu","year":"","journal-title":"Birth Defects Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"14759","DOI":"10.1038\/ncomms14759","article-title":"Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting","volume":"8","author":"Liu","year":"","journal-title":"Nat. Commun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1038\/nature08494","article-title":"Finding the missing heritability of complex diseases","volume":"461","author":"Manolio","year":"2009","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000337464","article-title":"Epidemiology of oral clefts 2012: an international perspective","volume":"16","author":"Mossey","year":"2012","journal-title":"Front. Oral Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1126\/science.1217876","article-title":"An abundance of rare functional variants in 202 drug target genes sequenced in 14, 002 people","volume":"337","author":"Nelson","year":"2012","journal-title":"Science"},{"key":"B32","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1177\/0022034517726079","article-title":"ARHGAP29 mutation is associated with abnormal oral epithelial adhesions","volume":"96","author":"Paul","year":"2017","journal-title":"J. Dent. Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1597\/10-178","article-title":"Genetics of nonsyndromic orofacial clefts","volume":"49","author":"Rahimov","year":"2012","journal-title":"Cleft Palate. Craniofac. J."},{"key":"B36","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B37","doi-asserted-by":"publisher","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":"B38","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1111\/cge.12823","article-title":"Impact of rare variants in ARHGAP29 to the etiology of oral clefts: role of loss-of-function vs missense variants","volume":"91","author":"Savastano","year":"2017","journal-title":"Clin. Genet."},{"key":"B39","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1146\/annurev-genom-083117-021641","article-title":"Rare-variant studies to complement genome-wide association studies","volume":"19","author":"Sazonovs","year":"2018","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"B40","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1038\/nmeth0810-575","article-title":"MutationTaster evaluates disease-causing potential of sequence alterations","volume":"7","author":"Schwarz","year":"2010","journal-title":"Nat. Methods"},{"key":"B41","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1093\/nar\/28.1.352","article-title":"dbSNP: a database of single nucleotide polymorphisms","volume":"28","author":"Smigielski","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/gm13","article-title":"The human gene mutation database: 2008 update","volume":"1","author":"Stenson","year":"2009","journal-title":"Genome Med."},{"key":"B43","doi-asserted-by":"publisher","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":"B44","doi-asserted-by":"publisher","first-page":"241","DOI":"10.5551\/jat.31393","article-title":"Common and rare variant association study for plasma lipids and coronary artery disease","volume":"23","author":"Tada","year":"2016","journal-title":"J. Atheroscler. Thromb."},{"key":"B45","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/s41576-019-0127-1","article-title":"Benefits and limitations of genome-wide association studies","volume":"20","author":"Tam","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"B46","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1126\/science.1219240","article-title":"Evolution and functional impact of rare coding variation from deep sequencing of human exomes","volume":"337","author":"Tennessen","year":"2012","journal-title":"Science"},{"key":"B47","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1002\/(sici)1096-8628(19980113)75:2<126::aid-ajmg2>3.0.co;2-r","article-title":"Classification and birth prevalence of orofacial clefts","volume":"75","author":"Tolarova","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"B48","doi-asserted-by":"publisher","first-page":"413","DOI":"10.2217\/pgs.13.36","article-title":"Rare-variant genome-wide association studies: a new frontier in genetic analysis of complex traits","volume":"14","author":"Wagner","year":"2013","journal-title":"Pharmacogenomics"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.clp.2018.07.006","article-title":"Cleft lip and palate","volume":"45","author":"Worley","year":"2018","journal-title":"Clin. Perinatol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1111\/odi.13566","article-title":"SNPs at TP63 gene was specifically associated with right-side cleft lip in Han Chinese population","volume":"27","author":"Yin","year":"2021","journal-title":"Oral Dis."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.947126\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T04:34:01Z","timestamp":1660710841000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.947126\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,17]]},"references-count":51,"alternative-id":["10.3389\/fgene.2022.947126"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.947126","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,17]]},"article-number":"947126"}}