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Genetic factors play a critical role in the pathogenesis of NSOFCs. However, known causal genes only explain a minority of the estimated heritability. To unveil the underlying genetic architecture, exome sequencing is performed on 214 sporadic patients with NSOFCs. The findings substantiate the genetic and allelic heterogeneity of NSOFCs and underscore the crucial role of dysregulation of OFC\u2010related signaling pathways in the occurrence of NSOFCs. Besides, the candidate variants discovered provide a fruitful resource for further genetic studies. Particularly, three\n                    <jats:italic>BOC<\/jats:italic>\n                    missense variants (p.R407W, p.G436S, and p.D1018N) are identified in three unrelated cases with cleft palate. In parallel, a\n                    <jats:italic>BOC<\/jats:italic>\n                    nonsense variant (p.R681X), co\u2010segregating with a\n                    <jats:italic>GLI2<\/jats:italic>\n                    missense variant (p.A543G), is identified in a multiplex family with microform cleft lip. Functional studies demonstrate while the four\n                    <jats:italic>BOC<\/jats:italic>\n                    variants are hypomorphic alleles, the\n                    <jats:italic>GLI2<\/jats:italic>\n                    variant is a hypermorphic allele. The counteraction between\n                    <jats:italic>BOC<\/jats:italic>\n                    p.R681X allele and\n                    <jats:italic>GLI2<\/jats:italic>\n                    p.A543G allele accounts for the mild phenotype in the multiplex family. Thus, this study establishes\n                    <jats:italic>BOC<\/jats:italic>\n                    as a novel causal gene and implicates a two\u2010locus model of inheritance via the epistatic antagonism of two SHH pathway variants in NSOFCs.\n                  <\/jats:p>","DOI":"10.1002\/advs.202412073","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T07:01:56Z","timestamp":1749020516000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exome Sequencing Reveals the Genetic Architecture of Non\u2010syndromic Orofacial Clefts and Identifies\n                    <i>BOC<\/i>\n                    as a Novel Causal Gene"],"prefix":"10.1002","volume":"12","author":[{"given":"Qing","family":"He","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology School of Basic Medical Sciences Health Science Center Xi'an Jiaotong University  Xi'an Shaanxi 710061 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