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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.

Key Points Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology. CLP affects approximately 1 in 700 live births, with wide variability across geographic origin, racial and ethnic groups, as well as environmental exposures and socioeconomic status. CLP can occur in syndromic or non-syndromic forms. This Review focuses on the latter. Although twin studies and familial clustering studies have provided compelling evidence for a genetic component to non-syndromic CLP, few pedigrees show clear-cut Mendelian inheritance and many cases appear to be sporadic. Accurate phenotyping is crucial to understanding both the epidemiology and aetiology of any congenital malformation because the power to detect effects is weakened when heterogeneous groups are treated as a single entity. To date, genetic approaches to non-syndromic CLP have included: linkage analysis using large, multiplex families or smaller but inbred families, or analysis of affected relative pairs; association studies using case–parent trios or case–control samples; identification of chromosomal anomalies or micro-deletions in cases; and direct sequencing of affected individuals. Genome-wide association studies have provided recent major advances in our understanding of genes and pathways that have a role in the aetiology of CLP. There is remarkable heterogeneity by ancestry in the relative contributions by genes found with common variants contributing to CLP. There is evidence that environmental factors have a role in CLP risk and interactions of the environment with certain genetic variants have been identified. The next critical phase of statistical analyses will be to examine the heterogeneity underlying the aetiology of oral clefts and to investigate the gene–gene and gene–environment interactions that control risk. Integration of genetic and environmental risk using epigenetics, systems biology, gene expression and epidemiology will be required to generate a synthesis that will both better characterize aetiologies and eventually lead to improvements in prevention and clinical care. Clefts of the lip and/or palate are common and have a complex genetic and environmental basis. Recent work on these birth defects illustrates the value of combining genome-wide association studies, animal models and improved clinical phenotyping. Future work may also address gene–environment interactions. Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology. CLP can occur in isolation or as part of a broad range of chromosomal, Mendelian or teratogenic syndromes. Although there has been marked progress in identifying genetic and environmental triggers for syndromic CLP, the aetiology of the more common non-syndromic (isolated) forms remains poorly characterized. Recently, using a combination of epidemiology, careful phenotyping, genome-wide association studies and analysis of animal models, several distinct genetic and environmental risk factors have been identified and confirmed for non-syndromic CLP. These findings have advanced our understanding of developmental biology and created new opportunities for clinical translational research.

Elisabeth Mangold and colleagues report a genome-wide meta-analyses of non-syndromic cleft lip with or without cleft palate (NSCL/P). They report six new genetic loci associated with risk for NSCL/P. We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; P NSCLP = 6.51 × 10 −11 ; homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84–3.16).

Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel ( RAD54B , TMEM19 , KRT18 , WNT9B , GSC / DICER1 , PTCH1 , RPS26 , OFCC1/TFAP2A , TAF1B , FGF10 , MSX1 , LINC00640 , FGFR1 and SPRY1 ). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation. Non-syndromic cleft lip with palate is a common birth defect of unknown aetiology. Here, the authors discover 14 new genes associated with this condition, and show genetic heterogeneity in this and other non-syndromic orofacial clefting disorders.

Nonsyndromic orofacial clefts (OFCs) are a heterogeneous group of common craniofacial birth defects with complex etiologies that include genetic and environmental risk factors. OFCs are commonly categorized as cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which have historically been analyzed as distinct entities. Genes for both CL/P and CP have been identified via multiple genome-wide linkage and association studies (GWAS); however, altogether, known variants account for a minority of the estimated heritability in risk to these craniofacial birth defects. We performed genome-wide meta-analyses of CL/P, CP, and all OFCs across two large, multiethnic studies. We then performed population-specific meta-analyses in sub-samples of Asian and European ancestry. In addition to observing associations with known variants, we identified a novel genome-wide significant association between SNPs located in an intronic TP63 enhancer and CL/P ( p  = 1.16 × 10 −8 ). Several novel loci with compelling candidate genes approached genome-wide significance on 4q21.1 ( SHROOM3 ), 12q13.13 ( KRT18 ), and 8p21 ( NRG1 ). In the analysis of all OFCs combined, SNPs near FOXE1 reached genome-wide significance ( p  = 1.33 × 10 −9 ). Our results support the highly heterogeneous nature of OFCs and illustrate the utility of meta-analysis for discovering new genetic risk factors.

François Spitz and colleagues identify cis -acting enhancers of Myc in a region orthologous to human 8q24 that are required for normal development of the face in mice. Their results shed light on the role of this region in facial deformities in humans, including cleft lip and palate. Cleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations observed in humans, with 1 occurrence in every 500–1,000 births 1 , 2 . A 640-kb noncoding interval at 8q24 has been associated with increased risk of non-syndromic CL/P in humans 3 , 4 , 5 , but the genes and pathways involved in this genetic susceptibility have remained elusive. Using a large series of rearrangements engineered over the syntenic mouse region, we show that this interval contains very remote cis -acting enhancers that control Myc expression in the developing face. Deletion of this interval leads to mild alteration of facial morphology in mice and, sporadically, to CL/P. At the molecular level, we identify misexpression of several downstream genes, highlighting combined impact on the craniofacial developmental network and the general metabolic capacity of cells contributing to the future upper lip. This dual molecular etiology may account for the prominent influence of variants in the 8q24 region on human facial dysmorphologies.

Elisabeth Mangold and colleagues report a genome-wide association study for non-syndromic cleft lip with or without cleft palate. We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 × 10 −8 , relative risk in homozygotes = 1.84, 95% CI 1.34–2.53) and 10q25.3 (rs7078160, combined P = 1.92 × 10 −8 , relative risk in homozygotes = 2.17, 95% CI 1.32–3.56).

Nonsyndromic orofacial clefts (OFCs) are common, heritable birth defects caused by both genetic and environmental risk factors. Despite the identification of many genetic loci harboring OFC-risk variants, there are many unknown genetic determinants of OFC. Furthermore, while the process of embryonic facial development is well characterized, the molecular mechanisms that underly it are not. This represents a major hurdle in understanding how disruptions in these biological processes result in OFC. Thus, we sought to identify novel OFC-risk loci through a genome-wide multi-ancestry study of five nested OFC phenotypes (isolated cleft lip [CLO], isolated cleft palate [CPO], cleft lip and palate [CLP], cleft lip with/without cleft palate [CL/P], and any cleft [ANY]) representing distinct cleft subtypes to identify subtype-specific signals and grouped types to maximize power to detect shared genetic effects. We performed genome-wide meta-analyses of these five OFC phenotypes from three cohorts totaling >14,000 individuals using METAL. In addition to replicating 13 known OFC-risk loci, we observed novel association in three regions: the 1p36.32 locus (lead variant rs584402, an intergenic variant, p CLO  = 3.14e-8), the 7q33 locus (lead variant rs17168118, an intronic variant in CALD1 , p CLP  = 9.17e-9), and the 16p13.3 locus (lead variant rs77075754, an intronic variant in RBFOX1 , p CL/P  = 1.53e-9, p ANY  = 1.93e-9). We also observed a novel association within the known risk locus 8q22.1 that was independent of the previously reported signal (lead variant rs4735314, an intronic variant in ESRP1 , p CLP  = 1.07e-9, p CL/P  = 3.88e-8). Next, we performed multi-tissue TWAS with s-MulTiXcan and identified four overlapping genes with significant genetically predicted transcription associated with OFC risk. These genes also overlapped the genome-wide significant association signals from the meta-analysis, including CALD1 and ESRP1 and known OFC-risk genes TANC2 and NTN1 . Each of the newly reported loci has potential regulatory effects, including evidence of craniofacial enhancer activity, that offer new clues as to the molecule mechanisms underlying embryonic facial development.

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1 -associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

Nonsyndromic cleft lip with or without a cleft palate (NSCL/P) is among the most common human congenital birth defects and imposes a substantial physical and financial burden on affected individuals. Here, we conduct a case–control-based GWAS followed by two rounds of replication; we include six independent cohorts from China to elucidate the genetic architecture of NSCL/P in Chinese populations. Using this combined analysis, we identify a new locus at 16p13.3 associated with NSCL/P: rs8049367 between CREBBP and ADCY9 (odds ratio=0.74, P =8.98 × 10 −12 ). We confirm that the reported loci at 1q32.2, 10q25.3, 17p13.1 and 20q12 are also involved in NSCL/P development in Chinese populations. Our results provide additional evidence that the rs2235371-related haplotype at 1q32.2 could play a more important role than the previously identified causal variant rs642961 in Chinese populations. These findings provide information on the genetic basis and mechanisms of NSCL/P. Cleft lip is one of the most common congenital birth defects with substantial impairments to quality of life. Here, Sun et al . identify a new locus associated with cleft lip in diverse Chinese populations.