Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

PLoS Genet. 2019 Oct 14;15(10):e1008357. doi: 10.1371/journal.pgen.1008357. eCollection 2019 Oct.


Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10-8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Brain / abnormalities*
  • Brain / physiopathology
  • Cleft Lip / genetics*
  • Cleft Lip / physiopathology
  • Cleft Palate / genetics*
  • Cleft Palate / physiopathology
  • Gene Dosage / genetics
  • Gene Expression Regulation / genetics
  • Gene Regulatory Networks / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Interferon Regulatory Factors / genetics*
  • PAX9 Transcription Factor / genetics*
  • Polymorphism, Single Nucleotide / genetics


  • IRF6 protein, human
  • Interferon Regulatory Factors
  • PAX9 Transcription Factor
  • PAX9 protein, human

Supplementary concepts

  • Orofacial Cleft 1

Grant support

This research project was supported by funding from the National Precision Medicine Project (grant 2016YFC0905200 to Z.Y. and grant 2017YFC0907302 to Y. S.) and the National Natural Science Foundation of China (grant 81970839 to L.H., grant 81670895 to L.H., grant 81300802 to L.H., grant 81430008 to Z.Y., grant 81790643 to Z.Y., grant 81570888 to Y.S., grant 81600849 to Z. J. and grant 81271118 to B.S.). The Department of Science and Technology of Sichuan Province also supported the work (grant 2014SZ0169 to Z.Y., grant 2015SZ0052 to Z. Y., grant 2015JQO057 to L.H., grant 2017JQ0024 to L.H., grant 2016HH0072 to L. H. and grant 2016JQ0026 to Y.S). The Top-Notch Young Talents Program of China supported Y.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.