Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft.

Lulin Huang,Haixin Wang,Fang Hao,Yiru Wang,He Lin,Qingwei Wang,Chenghao Li,Ziyan Wang,Jingtao Li,Bihe Zhang,Bing Shi,Zhenglin Yang,Yi Shi,Lin Zhang,Huijuan Xu,Qing Wang,Shijun Duan,Jiayu Shi,Dan Jiang,Bin Yin,Yandong Mou,Qing Du ,Edmond S.k ,Shuang Jiang ,Chengyue Yang ,Zhong‐Lin Jia ,Yan-Song Lin

doi:10.1371/journal.pgen.1008357

Abstract

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.

Highlights

Cleft lip and cleft palate are orofacial disruptions of the normal facial structure that can cause problems with feeding, speaking, hearing and social integration among affected individuals [1, 2]
genome-wide association study (GWAS) have discovered 43 genes/loci associated with nonsyndromic orofacial cleft (NSOFC), most previous studies used mixed samples of cleft palate (CL/P) subtypes rather than cleft palate only (CPO) or cleft lip only (CLO) separately
We identified 18 genes/loci that contribute to CPO, CLO or cleft palate (CLP)

Summary

Introduction

Cleft lip and cleft palate are orofacial disruptions of the normal facial structure that can cause problems with feeding, speaking, hearing and social integration among affected individuals [1, 2]. The majority of orofacial clefts lack additional defects in other tissues and are categorized as nonsyndromic cleft lip with or without cleft palate (CL/P) [5], which accounts for 70% of all orofacial clefts cases. CL/P cases include cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP) [6]. Asian and Native American ancestry populations generally exhibit the highest birth prevalence rates for nonsyndromic orofacial cleft (NSOFC), whereas European ancestry populations have intermediate prevalence rates, and African ancestry populations have the lowest prevalence rates [7]. The overall prevalence of NSOFC in China is 1.67 per 1,000 newborns, with rates for CPO (2.7), CLO (5.6) and CLP (8.2 per 10,000 newborns) [8]

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