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The identification of clinical patterns of tooth agenesis in individuals born with craniofacial deformities may be a useful tool for risk determination of these defects. We hypothesize that specific craniofacial deformities are associated with third molar agenesis. Objective The aim of this study was to identify if third molar agenesis could have a relation with other craniofacial structure alterations, such as cleft lip and palate, skeletal malocclusion, or specific growth patterns in humans. Design Data were obtained from 550 individuals ascertained as part of studies aiming to identify genetic contributions to oral clefts. 831 dental records of patients aged over eight years seeking orthodontic treatment were also included. SN-GoGn angle were used to classify the growth pattern (hypo-divergent, normal and hyper-divergent), and the ANB angle was used to verify the skeletal malocclusion pattern (Class I, II and III). Panoramic radiographs were used to determine third molar agenesis. Results A high frequency of third molar agenesis among individuals born with cleft lip with or without cleft palate (55%), as well as among their relatives (93.5%) was found. Third molar agenesis was not associated to skeletal malocclusion or growth pattern. Conclusion It appears that third molar agenesis is associated with the disturbances that lead to cleft lip and palate.

Molar incisor hypomineralization (MIH) is an enamel condition characterized by lesions ranging in color from white to brown which present rapid caries progression, and mainly affects permanent first molars and incisors. These enamel defects usually occur when there are disturbances during the mineralization or maturation stage of amelogenesis. Both genetic and environmental factors have been suggested to play roles in MIH’s development, but no conclusive risk factors have shown the source of the disease. During head and neck development, the interferon regulatory factor 6 (IRF6) gene is involved in the structure formation of the oral and maxillofacial regions, and the transforming growth factor alpha (TGFA) is an essential cell regulator, acting during proliferation, differentiation, migration and apoptosis. In this present study, it was hypothesized that these genes interact and contribute to predisposition of MIH. Environmental factors affecting children that were 3 years of age or older were also hypothesized to play a role in the disease etiology. Those factors included respiratory issues, malnutrition, food intolerance, infection of any sort and medication intake. A total of 1,065 salivary samples from four different cohorts were obtained, and DNA was extracted from each sample and genotyped for nine different single nucleotide polymorphisms. Association tests and logistic regression implemented in PLINK were used for analyses. A potential interaction between TGFA rs930655 with all markers tested in the cohort from Turkey was identified. These interactions were not identified in the remaining cohorts. Associations (p

Increased susceptibility to cleft lip, with or without cleft palate (CL±P) has been observed in South America, as related to Amerindian ancestry, using epidemiological data, uniparental markers, and blood groups. In this study, it was evaluated whether this increased risk remains when Amerindian ancestry is estimated using autosomal markers and considered in the predictive model. Ancestry was estimated through genotyping 62 insertion and deletion (INDEL) markers in sample sets of patients with CL±P, patients with cleft palate (CP), and controls, from Patagonia in southern Argentina and Belém in northern Brazil. The Amerindian ancestry in patients from Patagonia with CL±P was greater than in controls although it did not reach statistical significance. The European ancestry in patients with CL±P from Belém and in patients with CP from Belém and Patagonia was higher than in controls and statistically significant for patients with CP who were from Belém. This high contribution of European genetic ancestry among patients with CP who were from Belém has not been previously observed in American populations. Our results do not corroborate the currently accepted risks for CL±P and CP estimated by epidemiological studies in the North American populations and probably reflect the higher admixture found in South American ethnic groups when compared with the same ethnic groups from the North American populations.

Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis. Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs. Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10(-8)), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10(-8)). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10(-8)) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.