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PURPOSE: Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls. METHODS: We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria. RESULTS: 9.04% of cases and 1.02% of controls had "likely pathogenic" variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were "variants of uncertain significance", occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance. CONCLUSION: These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs.
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Labio Leporino , Fisura del Paladar , Humanos , Labio Leporino/diagnóstico , Labio Leporino/genética , Fisura del Paladar/diagnóstico , Fisura del Paladar/genética , Alelos , Mapeo Cromosómico , Factores Reguladores del Interferón/genéticaRESUMEN
Individuals with orofacial clefting (OFC) have a higher prevalence of tooth agenesis (TA) overall. Neither the precise etiology of TA, nor whether TA occurs in patterns that differ by gender or cleft type is yet known. This meta-analysis aims to identify the spectrum of tooth agenesis patterns in subjects with non-syndromic OFC and controls using the Tooth Agenesis Code (TAC) program. An indexed search of databases (PubMed, EMBASE, and CINAHL) along with cross-referencing and hand searches were completed from May to June 2019 and re-run in February 2022. Additionally, unpublished TAC data from 914 individuals with OFC and 932 controls were included. TAC pattern frequencies per study were analyzed using a random effects meta-analysis model. A thorough review of 45 records retrieved resulted in 4 articles meeting eligibility criteria, comprising 2182 subjects with OFC and 3171 controls. No TA (0.0.0.0) was seen in 51% of OFC cases and 97% of controls. TAC patterns 0.2.0.0, 2.0.0.0, and 2.2.0.0 indicating uni- or bi-lateral missing upper laterals, and 16.0.0.0 indicating missing upper right second premolar, were more common in subjects with OFC. Subjects with OFC have unique TA patterns and defining these patterns will help increase our understanding of the complex etiology underlying TA.
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Children with orofacial clefting (OFC) present with a wide range of dental anomalies. Identifying these anomalies is vital to understand their etiology and to discern the complex phenotypic spectrum of OFC. Such anomalies are currently identified using intra-oral exams by dentists, a costly and time-consuming process. We claim that automating the process of anomaly detection using deep neural networks (DNNs) could increase efficiency and provide reliable anomaly detection while potentially increasing the speed of research discovery. This study characterizes the use of` DNNs to identify dental anomalies by training a DNN model using intraoral photographs from the largest international cohort to date of children with nonsyndromic OFC and controls (OFC1). In this project, the intraoral images were submitted to a Convolutional Neural Network model to perform multi-label multi-class classification of 10 dental anomalies. The network predicts whether an individual exhibits any of the 10 anomalies and can do so significantly faster than a human rater can. For all but three anomalies, F1 scores suggest that our model performs competitively at anomaly detection when compared to a dentist with 8 years of clinical experience. In addition, we use saliency maps to provide a post-hoc interpretation for our model's predictions. This enables dentists to examine and verify our model's predictions.
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Aprendizaje Profundo , Niño , Estudios de Cohortes , Humanos , Redes Neurales de la Computación , Fotografía DentalRESUMEN
Enamel hypoplasia causes reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level. A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7-82 years. Mixed-models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts. Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (P < 5ï´10-8), and many suggestive association signals (5ï´10-8 < P < 5ï´10-6) near genes with plausible roles in tooth/enamel development. The strongest association signal (P = 1.57ï´10-9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.
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BACKGROUND: Dental caries is one of the most common chronic diseases and is influenced by a complex interplay of genetic and environmental factors. Most previous genetic studies of caries have focused on identifying genes that contribute to dental caries in specific ethnic groups, usually of European descent. METHODS: The aim of this study is to conduct a genome-wide association study (GWAS) to identify associations affecting susceptibility to caries in a large multiethnic population from Argentina, the Philippines, Guatemala, Hungary, and the USA, originally recruited for studies of orofacial clefts (POFC, N = 3686). Ages of the participants ranged from 2 to 12 years for analysis of the primary dentition, and 18-60 years for analysis of the permanent dentition. For each participant, dental caries was assessed by counts of decayed and filled teeth (dft/DFT) and genetic variants (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Caries was analyzed separately for the primary and permanent dentitions, with age, gender, and presence/absence of any type of OFC treated as covariates. Efficient Mixed-Model Association eXpedited (EMMAX) was used to test genetic association, while simultaneously accounting for relatedness and stratification. RESULTS: We identified several suggestive loci (5 × 10-8 < P < 5 × 10-6) within or near genes with plausible biological roles for dental caries, including a cluster of taste receptor genes (TAS2R38, TAS2R3, TAS2R4, TASR25) on chromosome 7 for the permanent dentition analysis, and DLX3 and DLX4 on chromosome 17 for the primary dentition analysis. Genome-wide significant results were seen with SNPs in the primary dentition only; however, none of the identified genes near these variants have known roles in cariogenesis. CONCLUSION: The results of this study warrant further investigation and may lead to a better understanding of cariogenesis in diverse populations, and help to improve dental caries prediction, prevention, and/or treatment in future.
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Labio Leporino , Fisura del Paladar , Caries Dental , Adolescente , Adulto , Niño , Preescolar , Índice CPO , Caries Dental/epidemiología , Caries Dental/genética , Femenino , Estudio de Asociación del Genoma Completo , Proteínas de Homeodominio , Humanos , Masculino , Persona de Mediana Edad , Filipinas , Factores de Transcripción , Adulto JovenRESUMEN
Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls. We observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance (p ≤ 0.05) and 52 segments at Bonferroni corrected significance (p < 1.2 × 10-3), respectively. Next, we quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. We identified 29 independent genetic loci that were associated (p < 5 × 10-8) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold (p < 8.47 × 10-10). Of the 29 loci, 22 were in proximity of loci previously associated with normal facial variation, 18 were near genes that show strong evidence in orofacial clefting (OFC), and another 10 showed some evidence in OFC. Additionally, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC.
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Odontogenesis is a complex process, where disruption can result in dental anomalies and/or increase the risk of developing dental caries. Based on previous studies, certain dental anomalies tend to co-occur in patients, suggesting that these traits may share common genetic and etiological components. The main goal of this study was to implement a multivariate genome-wide association study approach to identify genetic variants shared between correlated structural dental anomalies and dental caries. Our cohort (N = 3,579) was derived from the Pittsburgh Orofacial Clefts Study, where multiple dental traits were assessed in both the unaffected relatives of orofacial cleft (OFC) cases (n = 2,187) and unaffected controls (n = 1,392). We identified four multivariate patterns of correlated traits in this data: tooth agenesis, impaction, and rotation (AIR); enamel hypoplasia, displacement, and rotation (HDR); displacement, rotation, and mamelon (DRM); and dental caries, tooth agenesis and enamel hypoplasia (CAH). We analyzed each of these four models using genome-wide multivariate tests of association. No genome-wide statistically significant results were found, but we identified multiple suggestive association signals (P < 10-5) near genes with known biological roles during tooth development, including ADAMTS9 and PRICKLE2 associated with AIR; GLIS3, WDR72, and ROR2 associated with HDR and DRM; ROBO2 associated with DRM; BMP7 associated with HDR; and ROBO1, SMAD2, and MSX2 associated with CAH. This is the first study to investigate genetic associations for multivariate patterns of correlated dental anomalies and dental caries. Further studies are needed to replicate these results in independent cohorts.
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Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.
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Labio Leporino/genética , Fisura del Paladar/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Pueblo Asiatico/genética , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Población Blanca/genética , Secuenciación Completa del Genoma/métodosRESUMEN
Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least 'likely pathogenic', and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.
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Antígenos CD/genética , Encéfalo/anomalías , Cadherinas/genética , Labio Leporino/genética , Fisura del Paladar/genética , Predisposición Genética a la Enfermedad , Neoplasias Gástricas/genética , Encéfalo/patología , Labio Leporino/epidemiología , Labio Leporino/patología , Fisura del Paladar/epidemiología , Fisura del Paladar/patología , Femenino , Asesoramiento Genético , Mutación de Línea Germinal/genética , Humanos , Masculino , Linaje , Fenotipo , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/patologíaRESUMEN
AIM: The functional and structural complexities accompanying syndromic craniosynostosis make dental care for these patients particularly challenging. We report a case of long-term care for a syndromic craniosynostosis patient. The objective of this report is to introduce special care guidance and clinical recommendation, so that oral health care providers, as key members of a multidisciplinary care team, can provide optimal diagnosis, treatment, and management for the patient with syndromic craniosynostosis. CASE REPORT: The patient of this case report had a medical history of syndromic craniosynostosis involving multiple comorbidities. Over the past 20 years, a multidisciplinary care team has successfully treated the patient. Dental and medical procedures that the patient has received include cranial surgeries, prophylactic dental care, caries control, growth hormone therapy, comprehensive orthodontic treatment in conjunction with orthognathic surgeries, and plastic surgery. CONCLUSION: Oral health care providers can play essential roles in multidisciplinary care for patients with craniosynostosis by understanding the patients' unique oral health conditions and dentofacial deformities. To provide optimal oral health care in a multidisciplinary team, clear communication between the members of the care team is crucial.
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Craneosinostosis , Procedimientos de Cirugía Plástica , Humanos , SíndromeRESUMEN
Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.
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Proteínas Morfogenéticas Óseas/genética , Labio Leporino/diagnóstico , Labio Leporino/genética , Folistatina/metabolismo , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Factores de Diferenciación de Crecimiento/genética , Mutación , Alelos , Sustitución de Aminoácidos , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Línea Celular , Biología Computacional/métodos , Folistatina/química , Estudios de Asociación Genética/métodos , Genómica/métodos , Factores de Diferenciación de Crecimiento/antagonistas & inhibidores , Humanos , Modelos Moleculares , Linaje , Conformación Proteica , Secuenciación del ExomaRESUMEN
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G × S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G × S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test ( p < 1.00 × 10 -5 ) by examining the G × S effects from the same model. Out of the 133 loci with suggestive results ( p < 1.00 × 10 -5 ) for the joint test, we observed one genome-wide significant G × S effect in the 10q21 locus (rs72804706; p = 6.69 × 10 -9 ; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.
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Alelos , Encéfalo/anomalías , Labio Leporino/genética , Fisura del Paladar/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Caracteres Sexuales , Estudios de Casos y Controles , Epistasis Genética , Femenino , Frecuencia de los Genes/genética , Sitios Genéticos , Humanos , Masculino , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14% of multi-affected families and 2% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P.
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Cadherinas/genética , Cateninas/genética , Labio Leporino/genética , Fisura del Paladar/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Alelos , Secuencia de Aminoácidos , Animales , Biotinilación , Epitelio/metabolismo , Epitelio/patología , Femenino , Eliminación de Gen , Humanos , Lactante , Recién Nacido , Masculino , Ratones , Hueso Paladar/patología , Linaje , Síndrome , Secuenciación del Exoma , Catenina deltaRESUMEN
The biological relatives of offspring with nonsyndromic orofacial clefts have been shown to exhibit distinctive facial features, including excess asymmetry, which are hypothesized to indicate the presence of genetic risk factors. The significance of excess soft tissue nasal asymmetry in at-risk relatives is unclear and was examined in the present study. Our sample included 164 unaffected parents from families with a history of orofacial clefting and 243 adult controls. Geometric morphometric methods were used to analyze the coordinates of 15 nasal landmarks collected from three-dimensional facial surface images. Following generalized Procrustes analysis, Procrustes ANOVA and MANOVA tests were applied to determine the type and magnitude of nasal asymmetry present in each group. Group differences in mean nasal asymmetry were also assessed via permutation testing. We found that nasal asymmetry in both parents and controls was directional in nature, although the magnitude of the asymmetry was greater in parents. This was confirmed with permutation testing, where the mean nasal asymmetry was significantly different (p < .0001) between parents and controls. The asymmetry was greatest for midline structures and the nostrils. When subsets of parents were subsequently analyzed and compared (parents with bilateral vs. unilateral offspring; parents with left vs. right unilateral offspring), each group showed a similar pattern of asymmetry and could not be distinguished statistically. Thus, the side of the unilateral cleft (right vs. left) in offspring was not associated with the direction of the nasal asymmetry in parents.
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Fisura del Paladar/genética , Asimetría Facial/diagnóstico por imagen , Adulto , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Nariz/anomalías , Nariz/diagnóstico por imagen , PadresRESUMEN
Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes-cleft lip alone (CL) and CL plus cleft palate (CLP)-are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10-8 ). We also identified significant evidence of gene-gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs.
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Encéfalo/anomalías , Cromosomas Humanos Par 16 , Labio Leporino/genética , Fisura del Paladar/genética , Alelos , Encéfalo/patología , Labio Leporino/patología , Fisura del Paladar/patología , Femenino , Factores de Transcripción Forkhead/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple , Grupos Raciales/genética , Factores de RiesgoRESUMEN
PURPOSE: Meeting patient desires for enhanced facial esthetics requires that providers have standardized and objective methods to measure esthetics. The authors evaluated the effects of objective 3-dimensional (3D) facial shape and asymmetry measurements derived from 3D facial images on perceptions of facial attractiveness. MATERIALS AND METHODS: The 3D facial images of 313 adults in Iowa were digitized with 32 landmarks, and objective 3D facial measurements capturing symmetric and asymmetric components of shape variation, centroid size, and fluctuating asymmetry were obtained from the 3D coordinate data using geo-morphometric analyses. Frontal and profile images of study participants were rated for facial attractiveness by 10 volunteers (5 women and 5 men) on a 5-point Likert scale and a visual analog scale. Multivariate regression was used to identify the effects of the objective 3D facial measurements on attractiveness ratings. RESULTS: Several objective 3D facial measurements had marked effects on attractiveness ratings. Shorter facial heights with protrusive chins, midface retrusion, faces with protrusive noses and thin lips, flat mandibular planes with deep labiomental folds, any cants of the lip commissures and floor of the nose, larger faces overall, and increased fluctuating asymmetry were rated as significantly (P < .001) less attractive. CONCLUSION: Perceptions of facial attractiveness can be explained by specific 3D measurements of facial shapes and fluctuating asymmetry, which have important implications for clinical practice and research.
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Belleza , Cara/anatomía & histología , Imagenología Tridimensional/métodos , Adolescente , Adulto , Anciano , Puntos Anatómicos de Referencia , Femenino , Humanos , Iowa , Masculino , Persona de Mediana Edad , Programas InformáticosRESUMEN
INTRODUCTION: Genetic studies of malocclusion etiology have identified 4 deleterious mutations in genes DUSP6,ARHGAP21, FGF23, and ADAMTS1 in familial Class III cases. Although these variants may have large impacts on Class III phenotypic expression, their low frequency (<1%) makes them unlikely to explain most malocclusions. Thus, much of the genetic variation underlying the dentofacial phenotypic variation associated with malocclusion remains unknown. In this study, we evaluated associations between common genetic variations in craniofacial candidate genes and 3-dimensional dentoalveolar phenotypes in patients with malocclusion. METHODS: Pretreatment dental casts or cone-beam computed tomographic images from 300 healthy subjects were digitized with 48 landmarks. The 3-dimensional coordinate data were submitted to a geometric morphometric approach along with principal component analysis to generate continuous phenotypes including symmetric and asymmetric components of dentoalveolar shape variation, fluctuating asymmetry, and size. The subjects were genotyped for 222 single-nucleotide polymorphisms in 82 genes/loci, and phenotpye-genotype associations were tested via multivariate linear regression. RESULTS: Principal component analysis of symmetric variation identified 4 components that explained 68% of the total variance and depicted anteroposterior, vertical, and transverse dentoalveolar discrepancies. Suggestive associations (P < 0.05) were identified with PITX2, SNAI3, 11q22.2-q22.3, 4p16.1, ISL1, and FGF8. Principal component analysis for asymmetric variations identified 4 components that explained 51% of the total variations and captured left-to-right discrepancies resulting in midline deviations, unilateral crossbites, and ectopic eruptions. Suggestive associations were found with TBX1AJUBA, SNAI3SATB2, TP63, and 1p22.1. Fluctuating asymmetry was associated with BMP3 and LATS1. Associations for SATB2 and BMP3 with asymmetric variations remained significant after the Bonferroni correction (P <0.00022). Suggestive associations were found for centroid size, a proxy for dentoalveolar size variation with 4p16.1 and SNAI1. CONCLUSIONS: Specific genetic pathways associated with 3-dimensional dentoalveolar phenotypic variation in malocclusions were identified.
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Maloclusión/genética , Adolescente , Adulto , Anciano , Puntos Anatómicos de Referencia , Niño , Tomografía Computarizada de Haz Cónico , Femenino , Factor-23 de Crecimiento de Fibroblastos , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Análisis de Componente Principal , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: To examine maternal smoking and body mass index (BMI) interactions in contributing to risk of oral clefts. METHODS: We studied 4935 cases and 10,557 controls from six population-based studies and estimated a pooled logistic regression of individual-level data, controlling for study fixed effects and individual-level risk factors. RESULTS: We found a significant negative smoking-BMI interaction, with cleft risk with smoking generally declining with higher BMI. For all clefts combined, the odds ratio for smoking was 1.61 (95% confidence interval [CI]: 1.39-1.86) at BMI 17 (underweight), 1.47 (95% CI: 1.34-1.62) at BMI 22 (normal weight), 1.35 (95% CI: 1.22-1.48) at BMI 27 (overweight), 1.21 (95% CI: 1.04-1.41) at BMI 33 (obese), and 1.13 (95% CI: 0.92-1.38) at BMI 37 (very obese). A negative interaction was also observed for isolated clefts and across cleft types but was more pronounced for cleft lip only and cleft palate only. CONCLUSIONS: Our findings suggest that the risk of oral clefts associated with maternal smoking is largest among underweight mothers, although the smoking-BMI interaction is strongest for cleft lip only and cleft palate only. BMI was not protective for the effects of smoking; a clinically relevant increase in smoking-related cleft risk was still present among heavier women.
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Índice de Masa Corporal , Labio Leporino/etiología , Fisura del Paladar/etiología , Obesidad/complicaciones , Fumar/efectos adversos , Adolescente , Adulto , Estudios de Casos y Controles , Labio Leporino/epidemiología , Fisura del Paladar/epidemiología , Dinamarca/epidemiología , Femenino , Humanos , Modelos Logísticos , Noruega/epidemiología , Oportunidad Relativa , Embarazo , Primer Trimestre del Embarazo , Efectos Tardíos de la Exposición Prenatal , Factores de Riesgo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Background: Evidence on association of maternal pre-pregnancy weight with risk of orofacial clefts is inconsistent. Methods: Six large case-control studies of orofacial clefts from Northern Europe and the USA were included in analyses pooling individual-level data. Cases included 4943 mothers of children with orofacial clefts (cleft lip only: 1135, cleft palate with cleft lip: 2081, cleft palate only: 1727) and controls included 10 592 mothers of unaffected children. Association of orofacial cleft risk with pre-pregnancy maternal weight classified by level of body mass index (BMI, kg/m 2 ) was evaluated using logistic regression adjusting for multiple covariates. Results: Cleft palate, both alone and with cleft lip (CP+/-CL), was associated with maternal class II+ pre-pregnancy obesity (≥ 35)compared with normal weight [adjusted odds ratio (aOR) = 1.36; 95% confidence interval (CI) = 1.16, 1.58]. CP+/-CL was marginally associated with maternal underweight (aOR = 1.16; 95% CI = 0.98, 1.36). Cleft lip alone was not associated with BMI. Conclusions: In this largest population-based study to date, we found an increased risk of cleft palate, with or without cleft lip, in class II+ obese mothers compared with normal-weight mothers; underweight mothers may also have an increased risk, but this requires further study. These results also suggest that extremes of weight may have a specific effect on palatal development.