{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T14:40:24Z","timestamp":1793716824264,"version":"4.6.1"},"reference-count":32,"publisher":"SAGE Publications","issue":"12","license":[{"start":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T00:00:00Z","timestamp":1778889600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"National Science Funds of China","award":["81600849"],"award-info":[{"award-number":["81600849"]}]},{"name":"National Science Funds of China","award":["82170919"],"award-info":[{"award-number":["82170919"]}]},{"name":"Research and Develop Program, West China Hospital of Stomatology Sichuan University","award":["RD-03-202301"],"award-info":[{"award-number":["RD-03-202301"]}],"id":[{"id":"https:\/\/ror.org\/011ashp19","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100012542","name":"Sichuan Provincial Science and Technology Support Program","doi-asserted-by":"publisher","award":["2024NSFSC0649"],"award-info":[{"award-number":["2024NSFSC0649"]}],"id":[{"id":"10.13039\/100012542","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":[[2026,12]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To investigate Aristaless-like homeobox 4\n                      <jats:italic toggle=\"yes\">(<\/jats:italic>\n                      ALX4), a paired-like homeodomain transcription factor essential for craniofacial morphogenesis, as a susceptibility gene for non-syndromic orofacial cleft (NSOC) and to explore its potential regulatory mechanisms in the Han Chinese population.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>A two-stage case-control genetic association study complemented by exploratory RNA sequencing (RNA-seq) and functional validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>Tertiary medical center for orofacial cleft treatment in western China.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients, Participants<\/jats:title>\n                    <jats:p>Discovery phase: 2512 NSOC patients and 2255 controls. Replication phase: 2724 NSOC patients and 1263 controls. RNA-seq: 6 patients with non-syndromic cleft lip only (NSCLO) and 2 lip trauma controls. Real-time quantitative PCR (RT-qPCR) validation: 5 NSCLO patients and 5 controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interventions<\/jats:title>\n                    <jats:p>\n                      <jats:bold>:<\/jats:bold>\n                      Genotyping of 76 tag single-nucleotide polymorphisms (SNPs) within the ALX4 gene region using the SNPscan method, with three SNPs selected for independent replication. Exploratory RNA-seq of lip tissues, RT-qPCR validation, and dual-luciferase reporter assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main Outcome Measure(s)<\/jats:title>\n                    <jats:p>Allelic and genotypic associations between ALX4 variants and NSOC subtypes; differential expression of ALX4 and hsa-miR-455-3p in NSCLO tissues; functional validation of microRNA-target interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Multiple ALX4 SNPs showed significant associations with NSOC subtypes after Bonferroni correction (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009&lt;\u20096.58\u2009\u00d7\u200910\n                      <jats:sup>\u22124<\/jats:sup>\n                      ). rs3861063 demonstrated consistent protective effects for microform cleft lip across both phases. ALX4 and hsa-miR-455-3p were upregulated in NSCLO tissues, confirmed by RT-qPCR. Dual-luciferase assays confirmed that hsa-miR-455-3p directly targets the ALX4 3'UTR (untranslated region), though paradoxical co-upregulation suggests complex regulatory mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ALX4 is a novel NSOC susceptibility gene in Han Chinese, with subtype-specific genetic associations and a complex regulatory interaction involving hsa-miR-455-3p, expanding our understanding of NSOC genetic architecture.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10556656261452134","type":"journal-article","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T14:10:40Z","timestamp":1778940640000},"page":"4213-4223","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Association Between Variants Within Aristaless-Like Homeobox 4 and Non-syndromic Orofacial Cleft in Western Han Chinese"],"prefix":"10.1177","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3513-4222","authenticated-orcid":false,"given":"Yan","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Clinical Research Center for Oral Diseases &amp; Dept. of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3337-5250","authenticated-orcid":false,"given":"Si-Di","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Clinical Research Center for Oral Diseases &amp; Dept. of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Qi","family":"Ba","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Clinical Research Center for Oral Diseases &amp; Dept. of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2186-7052","authenticated-orcid":false,"given":"Yue","family":"You","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Clinical Research Center for Oral Diseases &amp; Dept. of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4624-7302","authenticated-orcid":false,"given":"Qian-Xue","family":"Wan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Clinical Research Center for Oral Diseases &amp; Dept. of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghao","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Clinical Research Center for Oral Diseases &amp; Dept. of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Shi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; 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