journal article·2025-08Open access

Exome Sequencing Reveals the Genetic Architecture of Non‐syndromic Orofacial Clefts and Identifies BOC as a Novel Causal Gene

Qing He, Min Yu, Yuhua Jiao, Yizhu Xu, Xuqin Liang, Wenbin Huang, Linping Xu, Yuxia Hou, Zhanping Ren, Beile Lyu, Zhenwei Qian, Pengpeng Liu, Jing Zhou, Huimei Huang, Chunyan Yin, Huaxiang Zhao, Yi Ding

Advanced Science· Volume 12· Issue 32

Abstract

Abstract Nonsyndromic orofacial clefts (NSOFCs) are the most common human craniofacial defects. 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‐related signaling pathways in the occurrence of NSOFCs. Besides, the candidate variants discovered provide a fruitful resource for further genetic studies. Particularly, three BOC missense variants (p.R407W, p.G436S, and p.D1018N) are identified in three unrelated cases with cleft palate. In parallel, a BOC nonsense variant (p.R681X), co‐segregating with a GLI2 missense variant (p.A543G), is identified in a multiplex family with microform cleft lip. Functional studies demonstrate while the four BOC variants are hypomorphic alleles, the GLI2 variant is a hypermorphic allele. The counteraction between BOC p.R681X allele and GLI2 p.A543G allele accounts for the mild phenotype in the multiplex family. Thus, this study establishes BOC as a novel causal gene and implicates a two‐locus model of inheritance via the epistatic antagonism of two SHH pathway variants in NSOFCs.
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Research context

OpenAlex topics: Cleft Lip and Palate Research · Hedgehog Signaling Pathway Studies · Congenital Ear and Nasal Anomalies

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Physiology and Pathophysiology School of Basic Medical Sciences Health Science Center Xi'an Jiaotong University Xi'an Shaanxi 710061 China

Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research College of Stomatology Xi'an Jiaotong University Xi'an Shaanxi 710004 China

Department of Prosthodontics Peking University School and Hospital of Stomatology National Center for Stomatology National Clinical Research Center for Oral Diseases National Engineering Research Center of Oral Biomaterials and Digital Medical Devices Beijing 100081 China

Department of Orthodontics College of Stomatology Xi'an Jiaotong University Xi'an Shaanxi 710004 China

Department of Orthodontics Stomatological Center Peking University Shenzhen Hospital Shenzhen Guangdong 518055 China

Department of Cleft Palate‐Craniofacial Surgery College of Stomatology Xi'an Jiaotong University Xi'an Shaanxi 710004 China

State Key Laboratory of Cellular Stress Biology School of Life Sciences Xiamen University Xiamen 361100 China

Peking University 302 Clinical Medical School Beijing 100039 China

Institute of Advanced Biotechnology Institute of Homeostatic Medicine and School of Medicine Southern University of Science and Technology Shenzhen 518055 China

Department of Pediatrics The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710004 China

Department of Nephrology Xi'an Children's Hospital The Affiliated Children's Hospital Xi'an Jiaotong University Xi'an Shaanxi 710003 China

Funding

National Natural Science Foundation of China · China Postdoctoral Science Foundation

References (56)

Show source-provided references
1. 10.1016/S0140-6736(09)60695-410.1016/S0140-6736(09)60695-4 ↗
2. Mossey P. A. · Front Oral Biol · 2012 · 16
3. 10.1038/s41576-023-00594-w10.1038/s41576-023-00594-w ↗
4. 10.1038/nrg293310.1038/nrg2933 ↗
5. 10.1242/dev.06708210.1242/dev.067082 ↗
6. 10.1111/odi.1417410.1111/odi.14174 ↗
7. 10.1002/bdr2.175410.1002/bdr2.1754 ↗
8. 10.1111/odi.1410910.1111/odi.14109 ↗
9. 10.1111/odi.1414610.1111/odi.14146 ↗
10. 10.1093/hmg/ddx01210.1093/hmg/ddx012 ↗
11. 10.1038/ncomms1436410.1038/ncomms14364 ↗
12. 10.1002/gepi.2221410.1002/gepi.22214 ↗
13. 10.12688/f1000research.9503.110.12688/f1000research.9503.1 ↗
14. 10.1038/s41576-019-0127-110.1038/s41576-019-0127-1 ↗
15. 10.1016/j.ajhg.2016.02.01310.1016/j.ajhg.2016.02.013 ↗
16. 10.1016/j.ajhg.2018.04.00910.1016/j.ajhg.2018.04.009 ↗
17. 10.1016/j.jgg.2023.03.01210.1016/j.jgg.2023.03.012 ↗
18. 10.1093/procel/pwae02110.1093/procel/pwae021 ↗
19. 10.1111/odi.1416410.1111/odi.14164 ↗
20. 10.1016/j.gim.2023.10091810.1016/j.gim.2023.100918 ↗
21. 10.1097/GOX.000000000000018610.1097/GOX.0000000000000186 ↗
22. 10.1038/s41596-024-01020-z10.1038/s41596-024-01020-z ↗
23. 10.1002/bdra.2359610.1002/bdra.23596 ↗
24. 10.1016/j.tig.2024.02.00410.1016/j.tig.2024.02.004 ↗
25. 10.1146/annurev-cellbio-100616-06084710.1146/annurev-cellbio-100616-060847 ↗
26. 10.1002/bdr2.201410.1002/bdr2.2014 ↗
27. 10.1002/dvdy.12210.1002/dvdy.122 ↗
28. 10.1242/dev.05795010.1242/dev.057950 ↗
29. 10.1002/cne.2050310.1002/cne.20503 ↗
30. 10.1038/s41580-023-00591-110.1038/s41580-023-00591-1 ↗
31. 10.1016/j.ydbio.2016.02.00910.1016/j.ydbio.2016.02.009 ↗
32. 10.1016/j.diff.2023.07.00210.1016/j.diff.2023.07.002 ↗
33. 10.1242/dmm.00574410.1242/dmm.005744 ↗
34. 10.1242/bio.2014798910.1242/bio.20147989 ↗
35. 10.1002/humu.2328610.1002/humu.23286 ↗
36. 10.1086/34441210.1086/344412 ↗
37. 10.1002/ajmg.c.3024010.1002/ajmg.c.30240 ↗
38. 10.1242/dmm.04027910.1242/dmm.040279 ↗
39. 10.1016/j.ebiom.2019.10.01610.1016/j.ebiom.2019.10.016 ↗
40. 10.1177/002203451664703410.1177/0022034516647034 ↗
41. 10.1177/002203451880153710.1177/0022034518801537 ↗
42. 10.1242/dev.18917510.1242/dev.189175 ↗
43. 10.1002/bdr2.163010.1002/bdr2.1630 ↗
44. 10.1097/ACI.000000000000010210.1097/ACI.0000000000000102 ↗
45. 10.1016/S0002-9297(07)64341-910.1016/S0002-9297(07)64341-9 ↗
46. 10.46234/ccdcw2021.19210.46234/ccdcw2021.192 ↗
47. 10.1016/j.gene.2024.14828010.1016/j.gene.2024.148280 ↗
48. 10.1016/j.gendis.2019.12.00310.1016/j.gendis.2019.12.003 ↗
49. 10.1038/gim.2015.3010.1038/gim.2015.30 ↗
50. 10.1002/humu.2408810.1002/humu.24088 ↗
51. 10.1093/bioinformatics/bty89710.1093/bioinformatics/bty897 ↗
52. 10.1016/j.ygeno.2022.11050710.1016/j.ygeno.2022.110507 ↗
53. 10.1073/pnas.210034211810.1073/pnas.2100342118 ↗
54. 10.1002/aja.100203030210.1002/aja.1002030302 ↗
55. 10.1038/nprot.2007.51410.1038/nprot.2007.514 ↗
56. 10.1016/j.ymeth.2013.04.01110.1016/j.ymeth.2013.04.011 ↗