Skeletal Class III phenotype: Link between animal models and human genetics: A scoping review.

This study aimed to identify evidence from animal studies examining genetic variants underlying maxillomandibular discrepancies resulting in a skeletal Class III (SCIII) malocclusion phenotype. Following the Manual for Evidence Synthesis of the JBI and the PRISMA extension for scoping reviews, a participant, concept, context question was formulated and systematic searches were executed in the PubMed, Scopus, WOS, Scielo, Open Gray, and Mednar databases. Of the 779 identified studies, 13 met the selection criteria and were included in the data extraction. The SCIII malocclusion phenotype was described as mandibular prognathism in the Danio rerio, Dicentrarchus labrax, and Equus africanus asinus models; and as maxillary deficiency in the Felis silvestris catus, Canis familiaris, Salmo trutta, and Mus musculus models. The identified genetic variants highlight the significance of BMP and TGF-ß signaling. Their regulatory pathways and genetic interactions link them to cellular bone regulation events, particularly ossification regulation of postnatal cranial synchondroses. In conclusion, twenty genetic variants associated with the skeletal SCIII malocclusion phenotype were identified in animal models. Their interactions and regulatory pathways corroborate the role of these variants in bone growth, differentiation events, and ossification regulation of postnatal cranial synchondroses.

Craniofacial syndromes and class III phenotype: common genotype fingerprints? A scoping review and meta-analysis.

Skeletal Class III (SCIII) is among the most challenging craniofacial dysmorphologies to treat. There is, however, a knowledge gap regarding which syndromes share this clinical phenotype. The aims of this study were to: (i) identify the syndromes affected by the SCIII phenotype; (ii) clarify the involvement of maxillary and/or mandibular structures; (iii) explore shared genetic/molecular mechanisms. A two-step strategy was designed: [Step#1] OMIM, MHDD, HPO, GeneReviews and MedGen databases were explored; [Step#2]: Syndromic conditions indexed in [Step#1] were explored in Medline, Pubmed, Scopus, Cochrane Library, WOS and OpenGrey. Eligibility criteria were defined. Individual studies were assessed for risk of bias using the New Ottawa Scale. For quantitative analysis, a meta-analysis was conducted. This scoping review is a hypothesis-generating research. Twenty-two studies met the eligibility criteria. Eight syndromes affected by the SCIII were targeted: Apert syndrome, Crouzon syndrome, achondroplasia, X-linked hypohidrotic ectodermal dysplasia (XLED), tricho-dento-osseous syndrome, cleidocranial dysplasia, Klinefelter and Down syndromes. Despite heterogeneity between studies [p < 0.05], overall effects showed that midface components were affected in Apert and Down Syndromes, lower face in Klinefelter Syndrome and midface and lower face components in XLED. Our review provides new evidence on the craniofacial characteristics of genetically confirmed syndromes exhibiting the SCIII phenotype. Four major regulatory pathways might have a modulatory effect on this phenotype. IMPACT: What does this review add to the existing literature? To date, there is no literature exploring which particular syndromes exhibit mandibular prognathism as a common trait. Through this research, it was possibly to identify the particular syndromes that share the skeletal Class III phenotype (mandibular prognathism) as a common trait highlighting the common genetic and molecular pathways between different syndromes acknowledging their impact in craniofacial development.

Genetic change investigation in DOCK1 gene in an Iranian family with sign and symptoms of temporomandibular joint disorder (TMD).

OBJECTIVES: Temporomandibular joint disorder (TMD) is a complex condition with pain and dysfunction in the temporomandibular joint and related muscles. Scientific evidence indicates both genetic and environmental factors play a crucial role in TMD. In this study, we aimed to discover the genetic changes in individuals from 4 generations of an Iranian family with signs and symptoms of TMD and malocclusion Class III. MATERIALS AND METHODS: Whole Exome Sequencing (WES) was performed in 4 patients (IV-8, IV-9, V-4, and V-6) with TMD according to (DC/TMD), along with skeletal Class III malocclusion. Then, PCR sequencing was performed on 23 family members to confirm the WES. RESULTS: In the present study, WES results analysis detected 6 heterozygous non-synonymous Single Nucleotide Variants (SNVs) in 5 genes, including CRLF3, DNAH17, DOCK1, SEPT9, and VWDE. A heterozygous variant, c.2012T > A (p.F671Y), in Exon 20 of the DOCK1 (NM_001290223.2) gene was identified. Then, this variant was investigated in 19 other members of the same family. PCR-Sequencing results showed that 7/19 had heterozygous TA genotype, all of whom were accompanied by malocclusion and TMD symptoms and 12/19 individuals had homozygous TT genotype, 9 of whom had no temporomandibular joint problems or malocclusion. The remaining 3 showed mild TMD clinical symptoms. The 5 other non-synonymous SNVs of CRLF3, DNAH17, SEPT9, and VWDE were not considered plausible candidates for TMD. CONCLUSIONS: The present study identified a heterozygous nonsynonymous c.2012T > A (p.F671Y) variant of the DOCK1 gene is significantly associated with skeletal class III malocclusion, TMD, and its severity in affected individuals in the Iranian pedigree. CLINICAL RELEVANCE: The role of genetic factors in the development of TMD has been described. The present study identified a nonsynonymous variant of the DOCK1 gene as a candidate for TMD and skeletal class III malocclusion in affected individuals in the Iranian pedigree.

Genetic architecture of non-syndromic skeletal class III malocclusion.

Non-syndromic skeletal Class III malocclusion is a major craniofacial disorder characterized by genetic and environmental factors. Patients with severe skeletal Class III malocclusion require orthognathic surgery to obtain aesthetic facial appearance and functional occlusion. Recent studies have demonstrated that susceptible chromosomal regions and genetic variants of candidate genes play important roles in the etiology of skeletal Class III malocclusion. Here, we provide a comprehensive review of our current understanding of the genetic factors that affect non-syndromic skeletal Class III malocclusion, including the patterns of inheritance and multiple genetic approaches. We then summarize the functional studies on related loci and genes using cell biology and animal models, which will help to implement individualized therapeutic interventions.

Genetic polymorphisms are involved in oral health-related quality of life in skeletal class III patients submitted to orthognathic surgery.

OBJECTIVE: This study aimed to evaluate whether sex and genetic polymorphisms impact the oral health-related quality of life (OHRQoL) preoperatively and the difference between preoperative and postoperative OHRQoL in skeletal Class III patients submitted to orthognathic surgery. MATERIALS AND METHODS: This longitudinal study consisted of ninety-nine patients with skeletal Class III malocclusion who required orthognathic surgery. The Oral Health Impact Profile-14 (OHIP-14) is a questionnaire used to assess the OHRQoL with a 5-point Likert-type scale, covering seven domains related to physical and psychosocial factors. The questionnaire was applied in the preoperative and postoperative periods, and the difference scores were calculated to assess the OHRQoL after orthognathic surgery. The DNA was extracted from oral mucosa cells to evaluate genetic polymorphisms in ANKK1, DRD2, ESR1, and ESR2 through real-time PCR. RESULTS: There was an improvement in all OHRQoL domains following orthognathic surgery (p < 0.05). In the preoperative evaluation, women presented worse OHRQoL (p < 0.05) than men. There was no statistical difference between sex and the OHRQoL after surgery (p > 0.05). When evaluating the polymorphisms and preoperative OHIP-14 scores, CT genotype patients for rs1800497 (ANKK1) had a worse perception of the physical pain domain than CC genotype (p = 0.026), and CC genotype patients for rs1256049 (ESR2) had a worse perception of the functional limitation domain than CT genotype (p = 0.002). In the analysis between polymorphisms and postoperative and preoperative difference scores, CT genotype patients for rs1256049 (ESR2) had a greater improvement in the perception of the physical pain domain than the CC genotype (p = 0.031). In rs6275 and rs6276 (DRD2), patients with the CC genotype worsened the perception of the functional limitation domain than the TT genotype (p = 0.045), and AA genotype patients worsened the perception of the functional limitation domain than GG genotype (p = 0.048) after surgery, respectively. In addition, patients with the CT genotype for rs1800497 (ANKK1) had a greater improvement of OHRQoL perception in the total scale than the TT genotype (p = 0.018), and CT genotype patients had a greater improvement in the perception of function limitation domain than TT genotype (p = 0.017). CONCLUSION: Women have a worse perception of OHRQoL in the preoperative period of orthognathic surgery. Furthermore, polymorphisms in the ANKK1, DRD2, and ESR2 genes could be involved with OHRQoL in the preoperative period and following orthognathic surgery. CLINICAL RELEVANCE: The knowledge of the genetic background concerning OHRQoL in skeletal class III patients would aid in clinical practice to screen for associated genetic factors and prevent OHRQoL deterioration, especially after orthognathic surgery, considering that patients' genetic profiles would soon be available.

Dissecting the Complexity of Skeletal-Malocclusion-Associated Phenotypes: Mouse for the Rescue.

Skeletal deformities and malocclusions being heterogeneous traits, affect populations worldwide, resulting in compromised esthetics and function and reduced quality of life. Skeletal Class III prevalence is the least common of all angle malocclusion classes, with a frequency of 7.2%, while Class II prevalence is approximately 27% on average, varying in different countries and between ethnic groups. Orthodontic malocclusions and skeletal deformities have multiple etiologies, often affected and underlined by environmental, genetic and social aspects. Here, we have conducted a comprehensive search throughout the published data until the time of writing this review for already reported quantitative trait loci (QTL) and genes associated with the development of skeletal deformation-associated phenotypes in different mouse models. Our search has found 72 significant QTL associated with the size of the mandible, the character, shape, centroid size and facial shape in mouse models. We propose that using the collaborative cross (CC), a highly diverse mouse reference genetic population, may offer a novel venue for identifying genetic factors as a cause for skeletal deformations, which may help to better understand Class III malocclusion-associated phenotype development in mice, which can be subsequently translated to humans. We suggest that by performing a genome-wide association study (GWAS), an epigenetics-wide association study (EWAS), RNAseq analysis, integrating GWAS and expression quantitative trait loci (eQTL), micro and small RNA, and long noncoding RNA analysis in tissues associated with skeletal deformation and Class III malocclusion characterization/phenotypes, including mandibular basic bone, gum, and jaw, in the CC mouse population, we expect to better identify genetic factors and better understand the development of this disease.

Genetic effect of single nucleotide polymorphisms in growth hormone receptor gene on the risk of non-syndromic mandibular prognathism in the Korean population.

OBJECTIVES: To evaluate the association of three single-nucleotide polymorphisms (SNPs) of growth hormone receptor (GHR) gene with mandibular prognathism (MP) and relationships between mandibular morphology and GHR gene SNPs in the Korean population. MATERIALS AND METHODS: A total of 325 subjects were divided into two groups based on sagittal maxillomandibular relationship by the lateral cephalography: the MP and control groups. From the SNPs in the GHR gene, three SNPs (rs6180, rs6182 and rs6184) were selected. SNP genotyping was performed using direct sequencing. The craniofacial measurements of lateral cephalography were analysed. RESULTS: We found a lack of association between GHR and MP. However, in the analysis according to the values of cephalometric measurements, rs6180 was significantly associated with ANB, SNB, effective mandibular length and SNMP in females. Additionally, rs6182 and rs6184 were significantly associated with ramal height in males. CONCLUSION: Growth hormone receptor SNPs may affect not only the sagittal development of mandible but also the vertical development of ramal height, and GHR SNPs may gender-differently influence mandibular morphology. This finding supports that the GHR might be susceptible on mandibular morphogenesis in the Korean population.

Koolen-de Vries syndrome in the first adulthood patient of Southern India ancestry.

Koolen-de Vries syndrome (KdVS, MIM#610443) is a rare malformation condition mainly characterized by cognitive impairment in association with craniofacial and visceral anomalies. The core phenotype is caused by mutations in the chromatin remodeler KANSL1 (MSL1V1, KIAA1267, KAT8 Regulatory NSL Complex Subunit 1, MIM#612452), which maps to 17q21.31 critical genomic region (Koolen et al., Nature Genetics 2012;44:639-641). Considering its molecular basis, KdVS is included in the group of Developmental Disorders of Chromatin Remodeling (DDCRs), also termed chromatinopathies. We describe the first KdVS patient of Southern India ethnicity, harboring the typical de novo 17q21.31 microdeletion, including KANSL1. Observed facial features and congenital anomalies are in line with the already reported KdVS phenotype, suggesting that phenotypic features are consistent across different ethnicities.

Potential interactions among single nucleotide polymorphisms in bone- and cartilage-related genes in skeletal malocclusions.

OBJECTIVE: To investigate SNPs in bone- and cartilage-related genes and their interaction in the aetiology of sagittal and vertical skeletal malocclusions. SETTINGS AND SAMPLE POPULATION: This study included 143 patients and classified as follows: skeletal class I (n = 77), class II (n = 47) and class III (n = 19); maxillary retrusion (n = 39), protrusion (n = 52) and well-positioned maxilla (n = 52); mandibular retrognathism (n = 50), prognathism (n = 50) and well-positioned mandible (n = 43); normofacial (n = 72), dolichofacial (n = 55) and brachyfacial (n = 16). MATERIALS AND METHODS: Steiner's ANB, SNA, SNB angles and Ricketts' NBa-PtGn angle were measured to determine the skeletal malocclusion and the vertical pattern. Nine SNPs in BMP2, BMP4, SMAD6, RUNX2, WNT3A and WNT11 were genotyped. Chi-squared test was used to compare genotypes among the groups. Multifactor dimensionality reduction (MDR) and binary logistic regression analysis, both using gender and age as co-variables, were also used. We performed Bonferroni correction for multiple testing. RESULTS: Significant associations at P < .05 were observed for SNPs rs1005464 (P = .042) and rs235768 (P = .021) in BMP2 with mandibular retrognathism and for rs59983488 (RUNX2) with maxillary protrusion (P = .04) as well as for rs708111 (WNT3A) with skeletal class III (P = .02; dominant model), rs1533767 (WNT11) with a brachyfacial skeletal pattern (P = .01, OR = 0.10; dominant model) and for rs3934908 (SMAD6) with prognathism (P = .02; recessive model). After the Bonferroni correction, none of the SNPs remained associated. The MDR predicted some interaction for skeletal class II, dolichofacial and brachyfacial phenotypes. CONCLUSION: Our results suggest that SNPs in BMP2, BMP4, SMAD6, RUNX2, WNT3A and WNT11 could be involved in the aetiology of sagittal and vertical malocclusions.

Genetic factors contributing to skeletal class III malocclusion: a systematic review and meta-analysis.

OBJECTIVES: The present systematic review aims to report and critically assess the findings of the available scientific evidence from genetic association studies examining the genetic variants underlying skeletal class III malocclusion and its sub-phenotypes. MATERIAL AND METHODS: A pre-piloted protocol was registered and followed. The PubMed, Scopus, WOS, Cochrane Library, Gray Open literature, and CADTH databases were explored for genetic association studies following PICOS-based selection criteria. The research was reported in accordance with PRISMA statement and HuGE guidelines. The Q-genie tool was applied to assess the quality of genetic studies. Meta-analysis of genetic association studies was done by means of Meta-Genyo tool. RESULTS: A total of 8258 articles were retrieved, of which 22 were selected for in-depth analysis. Most of the studies did not differentiate between sub-phenotypes, and the cohorts were heterogeneous regarding ethnicity. Four to five principal components of class III malocclusion explained the phenotypic variation, and gene variants at MYO1H(rs10850110), BMP3(rs1390319), GHR (rs2973015,rs6184, rs2973015), FGF7(rs372127537), FGF10(rs593307), and SNAI3(rs4287555) (p < .05) explained most of the variation across the studies, associated to vertical, horizontal, or combined skeletal discrepancies. Meta-analysis results identified a statistically significant association between risk of class III malocclusion of A allele of the FBN3 rs7351083 [OR 2.13; 95% CI 1.1-4.1; p 0.02; recessive model]. CONCLUSION: Skeletal class III is a polygenic trait substantially modulated by ethnicity. A multicentric approach should be considered in future studies to increase sample sizes, applying multivariate analysis such as PCA and cluster analysis to characterize existing sub-phenotypes warranting a deeper analysis of genetic variants contributing to skeletal class III craniofacial disharmony. CLINICAL RELEVANCE: Grasping the underlying mechanisms of this pathology is critical for a fuller understanding of its etiology, allowing generation of preventive strategies, new individualized therapeutic approaches and more accurate treatment planification strategies.

ADAMTSL1 and mandibular prognathism.

Mandibular prognathism is characterized by a prognathic or prominent mandible. The objective of this study was to find the gene responsible for mandibular prognathism. Whole exome sequencing analysis of a Thai family (family 1) identified the ADAMTSL1 c.176C>A variant as the potential defect. We cross-checked our exome data of 215 people for rare variants in ADAMTSL1 and found that the c.670C>G variant was associated with mandibular prognathism in families 2 and 4. Mutation analysis of ADAMTSL1 in 79 unrelated patients revealed the c.670C>G variant was also found in family 3. We hypothesize that mutations in ADAMTSL1 cause failure to cleave aggrecan in the condylar cartilage, and that leads to overgrowth of the mandible. Adamtsl1 is strongly expressed in the condensed mesenchymal cells of the mouse condyle, but not at the cartilage of the long bones. This explains why the patients with ADAMTSL1 mutations had abnormal mandibles but normal long bones. This is the first report that mutations in ADAMTSL1 are responsible for the pathogenesis of mandibular prognathism.

Is the "Habsburg jaw" related to inbreeding?

Background: The "Habsburg jaw" has long been associated with inbreeding due to the high prevalence of consanguineous marriages in the Habsburg dynasty. However, it is thought that mandibular prognathism (MP) is under the influence of a dominant major gene.Aim: To investigate the relationship between the "Habsburg jaw" and the pedigree-based inbreeding coefficient (F) as a relative measure of genome homozygosity.Subjects and methods: The degree of MP and maxillary deficiency (MD) of 15 members of the Habsburg dynasty was quantified through the clinical analysis of 18 dysmorphic features diagnosed from 66 portraits.Results: A statistically significant correlation (r = 0.711, p = 0.003) between MP and MD was observed among individuals. Only MP showed a statistically significant positive regression on F as evidenced from univariate analysis (b = 6.36 ± 3.34, p = 0.040) and multivariate analysis (PCA) performed from single dysmorphic features (b = 14.10 ± 6.62, p = 0.027, for the first PC).Conclusion: Both MP and MD are generally involved in the "Habsburg jaw." The results showed a greater sensitivity to inbreeding for the lower third of the face and suggest a positive association between the "Habsburg jaw" and homozygosity and therefore a basically recessive inheritance pattern.

Three novel genes tied to mandibular prognathism in eastern Mediterranean families.

INTRODUCTION: Mandibular prognathism (MP) is subject to major polygenic influence and segregates within families in autosomal dominance with variable expressivity and incomplete penetrance. We aimed to identify the inheritance pattern and genes and loci involved in the development of MP in Mediterranean families and to evaluate the dentoskeletal characteristics of affected individuals. METHODS: Fifty-one eastern Mediterranean families with individuals affected by MP were identified. Data and biospecimens were collected from 14 of the families, including clinical examination, lateral cephalography (on subjects with Class III malocclusion), and 5 mL blood drawn from consenting affected and nonaffected relatives. Next-generation sequencing (NGS) was performed on 8 families (7 Lebanese, 1 Lebanese/Syrian), including large numbers of affected individuals over many generations and severe conditions, with the use of whole-exome sequencing. RESULTS: Most pedigrees suggested autosomal-dominant inheritance with an equal number of affected male and female individuals. Affected individuals had macrognathic and prognathic mandibles with dentoalveolar compensation. Genetic screening did not correspond with previously reported MP-linked genes, but yielded 3 novel genes (C1orf167, NBPF8, NBPF9) on chromosome 1 potentially responsible for mandibular development and macrognathism. CONCLUSIONS: In this first genetic study with the use of NGS on the largest reported number of families with MP, novel genes (C1orf167, NBPF8, NBPF9) were associated with familial MP in the eastern Mediterranean population.

Genetic Etiology in Nonsyndromic Mandibular Prognathism.

Mandibular prognathism (MP) is considered to be a cranial-facial disorder resulting from the interaction between genes and environment. Recent studies have demonstrated that susceptible chromosomal regions and candidate genes may be responsible for MP. In this study, the authors present current views on the effect of genetic components in nonsystematic mandibular prognathism, in order to clarify the genetic etiology of MP. Data source were Electronic databases, manual searching, and reference lists checking, up to April 2016. Study selection, level of evidence assessment, and data extraction were done by 2 individuals in duplicate. Ninety-one studies were retrieved in initial electronic and manual search, and based on the established inclusion and exclusion criteria, 15 were selected for the review. In result, loci 1p36, 1q32.2, 1p22.3, 4p16.1, 6q25, 19p13, 14q24.3, 14q31.1, and 14q31.2 were thought to harbor genes that confer susceptibility to MP. Genes Matrilin-1, ADAMTS1, COL2A1, and EPB41 seemed to be strongly associated with MP while gene of growth hormone receptor was in dispute. Genetic components appeared to be associated with MP. However, in view of the variety of populations and results in related publications, further studies are necessary to clarify the genetic etiology of MP.

Genetic Factors Involved in Mandibular Prognathism.

Mandibular prognathism is defined as an abnormal forward projection of the mandible beyond the standard relation to the cranial base and it is usually categorized as both a skeletal Class III pattern and Angle Class III malocclusion. The etiology of mandibular prognathism is still uncertain, with various genetic, epigenetic, and environmental factors possibly involved. However, many reports on its coexistence in both twins and segregation in families suggest the importance of genetic influences. A multifactorial and polygenic background with a threshold for expression or an autosomal dominant mode with incomplete penetrance and variable expressivity are the most probable inheritance patterns. Linkage analyses have, thus far, shown the statistical significance of such loci as 1p22.1, 1p22.3, 1p32.2, 1p36, 3q26.2, 4p16.1, 6q25, 11q22, 12pter-p12.3, 12q13.13, 12q23, 12q24.11, 14q24.3 to 31.2, and 19p13.2. The following appear among candidate genes: MATN1, EPB41, growth hormone receptor, COL2A1, COL1A1, MYO1H, DUSP6, ARHGAP21, ADAMTS1, FGF23, FGFR2, TBX5, ALPL, HSPG2, EVC, EVC2, the HoxC gene cluster, insulin-like growth factor 1, PLXNA2, SSX2IP, TGFB3, LTBP2, MMP13/CLG3, KRT7, and FBN3. On the other hand, MYH1, MYH2, MYH3, MYH7, MYH8, FOXO3, NFATC1, PTGS2, KAT6B, HDAC4, and RUNX2 expression is suspected to be involved in the epigenetic regulations behind the mandibular prognathism phenotype.

Genome-wide association study for mandibular prognathism using microsatellite and pooled DNA method.

INTRODUCTION: The purpose of this study was to extend an association study from chromosome 1 to the whole genome (genome-wide association study) to find susceptibility loci of mandibular prognathism. METHODS: Two hundred forty patients diagnosed with mandibular prognathism and 360 healthy controls of Japanese descent were recruited. The typing of microsatellites covering the whole genome was conducted using a pooled DNA method. Upon completion of the first and second screenings with pooled DNA, the positive microsatellite markers from both the first and second typings were retyped using individual-subject DNA samples to confirm the significance of allele frequency. RESULTS: Six microsatellites (D1S0411i, D1S1358i, D3S0810i, D6S0827i, D7S0133i, and D15S0154i) showed differences between allele frequencies of the subjects and controls at P <0.001. D1S0411i, D1S1358i, D3S0810i, D6S0827i, D7S0133i, and D15S0154i were located on chromosomes 1p22.3, 1q32.2, 3q23, 6q23.2, 7q11.22, and 15q22.22, respectively. SSX2IP, PLXNA2, RASA2, TCF21, CALN1, and RORA were suggested as candidate genes. CONCLUSIONS: The genome-wide association study using microsatellites suggested that 6 loci (1p22.3, 1q32.2, 3q23, 6q23.2, 7q11.22, and 15q22.22) were susceptibility regions of mandibular prognathism. The locus 1p22.3 was supported by a previous linkage analysis, and the other 5 were novel loci.

Genetic polymorphisms underlying the skeletal Class III phenotype.

INTRODUCTION: Our goal was to verify the association between candidate polymorphisms and skeletal Class III malocclusion in a well-characterized homogeneous sample set. METHODS: Thirty-five single-nucleotide polymorphisms were studied from 10 candidate loci in 54 Class III subjects and 120 controls. Skeletal Class III characteristics included ANB angle less than 0°, SNB angle greater than 83° (mandibular prognathism), SNA angle less than 79° (maxillary deficiency), Class III molar relationship, and negative overjet. Inclusion criteria for the controls were ANB angle between 0° and 4°, Class I molar relationship, and normal overjet. Chi-square and Fisher exact tests and principal component (PC) analysis were used to determine overrepresentation of marker alleles with alpha of 0.05. Odds ratios and 95% confidence intervals were calculated. RESULTS: MYO1H (rs10850110 AG) (P = 0.001) with PC2 and between FGF10 (rs593307 A

[Legend, art and medicine]. / Légende, art et medicine.

The study of the heredity of mandibular proganthism has curiously been initiated by a legend and by the examination of a Brussels tapestry. The hereditary condition of mandibular prognathism was recognized by the study of numerous iconographic documents concerning the Habsburger family. Charles V was the most representative of this anomaly of the lower jaw. Numerous members of the Spanish House and of the Austrian House were afflicted with mandibular prognathism. Family intermarriages promoted the multiplication of mandibular anomaly in those important families.

L'étude de l'hérédité de la prognathie mandibulaire a curieusement été initiée par une légende et par l'examen d'une tapisserie de Bruxelles. L'étude de documents iconographiques de la famille des Habsbourg a permis de démontrer le caractère héréditaire de cette malformation. Charles Quint fut le représentant le plus caractéristique. De nombreux membres des Maisons d'Espagne et d'Autriche étaient prognathes. Les mariages consanguins ont permis la multiplication de cette hypertrophie de la mâchoire inférieure dans ces familles importantes.

Genetics of the dentofacial variation in human malocclusion.

Malocclusions affect individuals worldwide, resulting in compromised function and esthetics. Understanding the etiological factors contributing to the variation in dentofacial morphology associated with malocclusions is the key to develop novel treatment approaches. Advances in dentofacial phenotyping, which is the comprehensive characterization of hard and soft tissue variation in the craniofacial complex, together with the acquisition of large-scale genomic data have started to unravel genetic mechanisms underlying facial variation. Knowledge on the genetics of human malocclusion is limited even though results attained thus far are encouraging, with promising opportunities for future research. This review summarizes the most common dentofacial variations associated with malocclusions and reviews the current knowledge of the roles of genes in the development of malocclusions. Lastly, this review will describe ways to advance malocclusion research, following examples from the expanding fields of phenomics and genomic medicine, which aim to better patient outcomes.

Epigenetic influence of KAT6B and HDAC4 in the development of skeletal malocclusion.

INTRODUCTION: Genetic influences on the development of malocclusion include heritable effects on both masticatory muscles and jaw skeletal morphology. Beyond genetic variations, however, the characteristics of muscle and bone are also influenced by epigenetic mechanisms that produce differences in gene expression. We studied 2 enzymes known to change gene expressions through histone modifications, chromatin-modifying histone acetyltransferase KAT6B and deacetylase HDAC4, to determine their associations with musculoskeletal variations in jaw deformation malocclusions. METHODS: Samples of masseter muscle were obtained from subjects undergoing orthognathic surgery from 6 malocclusion classes based on skeletal sagittal and vertical dysplasia. The muscles were characterized for fiber type properties by immunohistochemistry, and their total RNA was isolated for gene expression studies by microarray analysis and quantitative real-time polymerase chain reaction. RESULTS: Gene expressions for fast isoforms of myosins and contractile regulatory proteins and for KAT6B and HDAC4 were severalfold greater in masseter muscles from a patient with a deepbite compared with one with an open bite, and genes related to exercise and activity did not differ substantially. In the total population, expressions of HDAC4 (P = 0.03) and KAT6B (P = 0.004) were significantly greater in subjects with sagittal Class III than in Class II malocclusion, whereas HDAC4 tended to correlate negatively with slow myosin type I and positively with fast myosin gene, especially type IIX. CONCLUSIONS: These data support other published reports of epigenetic regulation in the determination of skeletal muscle fiber phenotypes and bone growth. Further investigations are needed to elucidate how this regulatory model might apply to musculoskeletal development and malocclusion.