Preface to the 9th Biennial COAST Conference: Harnessing Technology and Biomedicine for Personalized Orthodontics.

OBJECTIVE: The Consortium on Orthodontic Advances in Science and Technology (COAST) convened for its 9th biennial conference titled 'Harnessing Technology and Biomedicine for Personalized Orthodontics' to explore cutting-edge craniofacial research towards building the foundations for precision care in orthodontics. SETTING AND SAMPLE POPULATION: Seventy-five faculty, scholars, private practitioners, industry, residents and students met at the UCLA Arrowhead Lodge on 6-9 November 2022 for networking, scientific presentations and facilitated discussions. Thirty-three speakers provided state-of-the-art, evidence-based scientific and perspective updates in craniofacial and orthodontic-related fields. The overall format included an Education Innovation Award Faculty Development Career Enrichment (FaCE) workshop focused on faculty career development, three lunch and learns, keynote or short talks and poster presentations. MATERIAL AND METHODS: The 2022 COAST Conference was organized thematically to include (a) genes, cells and environment in craniofacial development and abnormalities; (b) precision modulation of tooth movement, retention and facial growth; (c) applications of artificial intelligence in craniofacial health; (d) precision approaches to Sleep Medicine, OSA and TMJ therapies; and (e) precision technologies and appliances. RESULTS: The collective advances in orthodontics and science represented in the manuscripts of this issue fulfil our goal of laying solid foundations for personalized orthodontics. Participants elevated the need for stronger industry-academic research partnerships to leverage knowledge gained from large datasets with treatment approaches and outcomes; systematizing the potential of big data including through multi-omics and artificial intelligence approaches; refining the genotype: phenotype correlation to create biotechnology that will rescue inherited dental and craniofacial defects; evolving studies of tooth movement, sleep apnoea and TMD treatment to accurately measure dysfunction and treatment successes; and maximizing the integration of newer orthodontic devices and digital workflows. CONCLUSIONS: Technological advances combined with those in biomedicine and machine learning are rapidly changing the delivery of health care including that in orthodontics. These advances promise to lead to enhanced customization, efficiencies and outcomes of patient care in routine orthodontic problems and in severe craniofacial problems, OSA and TMD.

Using a digital platform to establish odontometric variation based on race, gender and Angle classification.

Orthodontists often encounter significant clinical challenges in the finishing stages of treatment due to a disproportion in interarch tooth size relationships. Despite the increasing presence of digital technology and concomitant focus on customized treatment approaches, there is a gap in the knowledge of how generating tooth size data using digital versus traditional methods may impact our treatment regime. OBJECTIVE: This study aimed to compare the prevalence of tooth size discrepancies using digital models and a digitally based cast analysis in our cohort based on (i) Angle's Classification; (ii) gender and (iii) race. MATERIALS AND METHODS: The mesiodistal widths of teeth in 101 digital models were assessed using computerized odontometric software. A Chi-square test was used to determine the prevalence of tooth size disproportions among the study groups. The differences between all three groups of the cohort were analysed using a three-way analysis of variance (ANOVA). RESULTS: An overall Bolton tooth size discrepancy (TSD) prevalence of 36.6% was observed in our study cohort; 26.7% had an anterior Bolton TSD. No differences existed in the prevalence of tooth size discrepancies between male and female subjects as well as between the different malocclusion groups (P > .05). Caucasian subjects had a statistically significant smaller prevalence of TSD compared to Black and Hispanic patients (P < .05). CONCLUSION: The prevalence results in this study illuminate how relatively common TSD is and underscores the importance of proper diagnosis. Our findings also suggest that racial background may be an influential factor in the presence of TSD.

Nine Novel PAX9 Mutations and a Distinct Tooth Agenesis Genotype-Phenotype.

Tooth agenesis is one of the most common developmental anomalies affecting function and esthetics. The paired-domain transcription factor, Pax9, is critical for patterning and morphogenesis of tooth and taste buds. Mutations of PAX9 have been identified in patients with tooth agenesis. Despite significant progress in the genetics of tooth agenesis, many gaps in knowledge exist in refining the genotype-phenotype correlation between PAX9 and tooth agenesis. In the present study, we complete genetic and phenotypic characterization of multiplex Chinese families with nonsyndromic (NS) tooth agenesis. Direct sequencing of polymerase chain reaction products revealed 9 novel (c.140G>C, c.167T>A, c.332G>C, c.194C>A, c.271A>T, c.146delC, c.185_189dup, c.256_262dup, and c.592delG) and 2 known heterozygous mutations in the PAX9 gene among 120 probands. Subsequently, pedigrees were extended, and we confirmed that the mutations co-segregated with the tooth agenesis phenotype (with exception of families in which DNA analysis was not available). In 1 family ( n = 6), 2 individuals harbored both the PAX9 c.592delG mutation and a heterozygous missense mutation (c.739C>T) in the MSX1 gene. Clinical characterization of families segregating a PAX9 mutation reveal that all affected individuals were missing the mandibular second molar and their maxillary central incisors are most susceptible to microdontia. A significant reduction of bitter taste perception was documented in individuals harboring PAX9 mutations ( n = 3). Functional studies revealed that PAX9 haploinsufficiency or a loss of function of the PAX9 protein underlies tooth agenesis.

Preface to COAST 2016 innovators' workshop on personalized and precision orthodontic therapy.

OBJECTIVE: A second focused workshop explored how to transfer novel findings into clinical orthodontic practice. SETTING AND SAMPLE POPULATION: Participants met in West Palm Beach (Florida, USA), on 9-11 September 2016 for the Consortium for Orthodontic Advances in Science and Technology 2016 Innovators' Workshop (COAST). Approximately 65 registered attendees considered and discussed information from 27 to 34 speakers, 8 to 15 poster presenters and four lunch-hour focus group leaders. MATERIAL AND METHODS: The innovators' workshops were organized according to five themed sessions. The aims of the discussion sessions were to identify the following: i) the strength and impact of the evidenced-based discoveries, ii) required steps to enable further development and iii) required steps to translate these new discoveries into orthodontic practice. RESULTS: The role of gene-environment interactions that underlie complex craniofacial traits was the focus of several sessions. It was agreed that diverse approaches are called for, such as (i) large-scale collaborative efforts for future genetic studies of complex traits; (ii) deep genome sequencing to address the issues of isolated mutations; (iii) quantifying epigenetic-environmental variables in diverse areas myofascial pain, alveolar remodelling and mandibular growth. Common needs identified from the themed sessions were multiscale/multispecies modelling and experimentation using controlled and quantified mechanics and translation of the findings in bone biology between species. Panel discussions led to the consensus that a consortium approach to establish standards for intra-oral scanning and 3D imaging should be initiated. CONCLUSIONS: Current and emerging technologies still require supported research to translate new findings from the laboratory to orthodontic practice.

A new cyte in orthodontics: Osteocytes in tooth movement.

Orthodontic tooth movement (OTM) relies on the orchestration of clinical and biologic events that include the application of clinical force followed by a cascade of cellular and molecular responses. Our understanding about OTM today has evolved from, and is largely based on historic studies. However, the advances in bone biology and clinical orthodontics today continue to pave the pathway towards an improved knowledge base, and state of the art therapeutics in OTM. Osteoblasts and osteoclasts have been the primary cells analyzed in OTM. However, the role of osteocytes, a cell previously thought to be static, should be considered in light of new findings in molecular biological research. Osteocytes are now known to be significant in controlling responses to mechanical forces and therefore may be central to both OTM and normal tooth eruption. In this review, we explore the biology of OTM by focusing specifically on the potential role of osteocytes. Evidence from recent studies reveal that osteocytes have a role in controlling the response to mechanical forces and OTM. We therefore propose that these findings and further research endeavours may shape the future of clinical applications-specifically enhanced outcomes in OTM.

In silico and functional evaluation of PTH1R mutations found in patients with primary failure of eruption (PFE).

OBJECTIVES: The genetic basis of PFE (OMIM ID: 125350) was interrogated using molecular functional studies. PFE is a disorder that results in a poor prognosis in the eruption of teeth and by extension, in treatment with a continuous archwire. We tested the hypothesis that PTH1R mutations result in loss of function due to altered protein structure to determine (i) the fate of a functional PTH1R mutation and (ii) the resulting PTH1R protein structure of each functional mutation. METHODS: We used immunofluorescence assay of COS7 cells that were transfected with either the WT or 1092delG PTH1R mutation sequence to compare the fate of the expressed protein. We also performed in silico analysis of the WT PTH1R and four different functional PTH1R mutations RESULTS: Functional studies (IFA) showed a variation in expression between the WT and mutant PTH1R. Further, in silico analysis showed structural differences between WT and mutant PTH1R proteins, particularly in the regions of the 3rd intracellular loop and the 6th transmembrane domain required for efficient PTH1R function. CONCLUSION: PTH1R mutations identified in PFE likely result from diminished function due to truncation of the protein, lack of efficient G-protein interactions and putatively attenuated signal transduction. By identifying the mode of protein dysfunction, scientist-clinicians are better prepared to recognize and thereby develop improved methods of treatment, starting at the molecular level.

Personalized and precision orthodontic therapy.

OBJECTIVE: To bring together orthodontic stakeholders from academics, industry, and private practice for a series of thematically focused workshops to explore and develop the transfer of novel approaches into clinical orthodontic practice. SETTING AND SAMPLE POPULATION: Twenty-seven invited speakers, eight poster presenters, and participants of the Consortium for Orthodontic Advances in Science and Technology (COAST) 2014 Innovators' Workshop at the Eaglewood Resort and Spa, Itasca, Illinois, September 11-14, 2014. MATERIAL AND METHODS: Five themed sessions involving between 4-7 presentations followed by panel discussions were organized. The aims of the discussion sessions were to highlight important findings and consider the strength of evidence for these, indicate next steps and needed research or technological developments to move forward, and to weigh the expected benefits from these findings and steps to implement in clinical practice. RESULTS: Among important areas for attention identified were need for multiscale and multispecies modeling and experimentation for interspecies translation of results; large-scale collaborative efforts within the profession to address the need for adequate sample sizes for future genetic studies of complex traits such as malocclusion; a consortium approach to improve new technologies such as intra-oral scanning and 3D imaging by establishing standards; and harnessing the growing body of knowledge about bone biology for application in orthodontics. CONCLUSIONS: With increased awareness of the potential of current and emerging technologies, translation of personalized and precision approaches in the field of orthodontics holds ever-increasing promise.

Characterization of short root anomaly in a Mexican cohort--hereditary idiopathic root malformation.

OBJECTIVE: The purpose of this study was to systematically characterize individuals with short root anomaly (SRA) without any history of orthodontic treatment. The long-term objective of the study was to improve diagnosis and treatment planning and determine risk factors for developing SRA. SETTING AND SAMPLE POPULATION: Twenty-seven patients including two families and 16 unrelated individuals from (9-48 years) reported to orthodontic and/or dental practitioners within the USA. MATERIALS AND METHODS: Digital panoramic and periapical films were analyzed to document pattern and frequency of SRA-affected teeth. Crown-to-root (CR) ratios of the affected teeth were used to characterize the extent of malformation. Pedigree analysis by inspection was completed for one family to determine pattern of inheritance. RESULTS: Twenty-six of the twenty-seven individuals were of Latino descent, and one was of Filipino descent. Hard tissues including enamel, dentin, pulp chambers and canals, and surrounding soft tissues were normal. We found that 25 of 27 individuals had localized SRA and two Latino individuals had generalized SRA. Teeth were affected bilaterally with maxillary central incisors (~63%) and mandibular second premolars most commonly involved (~33%). Affected teeth had a distinct, similar radiographic appearance; in the generalized cases, there was a more severe affection with larger (~twice) CR ratios. Ninety-four percent of affected individuals did not show a significant difference in the CR ratios at different ages. Pedigree analysis suggests an autosomal dominant inheritance pattern in one family. CONCLUSION: This is the first report to show that SRA occurs more frequently in Latino individuals and has a predilection for anterior teeth. The occurrence of SRA in two families further confirms a hereditary component and supports a distinct nosology and nomenclature, hereditary idiopathic root malformation (HIRM) and warrants further investigation.

Novel mutations in PTH1R associated with primary failure of eruption and osteoarthritis.

Autosomal dominant mutations in PTH1R segregate with primary failure of eruption (PFE), marked by clinical eruption failure of adult teeth without mechanical obstruction. While the diagnosis of PFE conveys a poor dental prognosis, there are no reports of PFE patients who carry PTH1R mutations and exhibit any other skeletal problems. We performed polymerase chain reaction-based mutational analysis of the PTH1R gene to determine the genetic contribution of PTH1R in 10 families with PFE. Sequence analysis of the coding regions and intron-exon boundaries of the PTH1R gene in 10 families (n = 54) and 7 isolated individuals revealed 2 novel autosomal dominant mutations in PTH1R (c.996_997insC and C.572delA) that occur in the coding region and result in a truncated protein. One family showed incomplete penetrance. Of 10 families diagnosed with PFE, 8 did not reveal functional (nonsynonymous) mutations in PTH1R; furthermore, 4 families and 1 sporadic case carried synonymous single-nucleotide polymorphisms. Five PFE patients in 2 families carried PTH1R mutations and presented with osteoarthritis. We propose that the autosomal dominant mutations of PTH1R that cause PFE may also be associated with osteoarthritis; a dose-dependent model may explain isolated PFE and osteoarthritis in the absence of other known symptoms in the skeletal system.

Mechanism and control of tooth eruption: overview and clinical implications.

OBJECTIVES: To review pre- and post-emergent eruption, with particular emphasis on distinguishing isolated molar ankylosis from primary failure of eruption (PFE) and genetic considerations in eruption problems. MATERIAL AND METHODS: Radiographic review of eruption failure patients; animal and human experiments; high precision observations of movements of erupting teeth. RESULTS: In pre-emergent tooth eruption, the controlling element is the rate of resorption of overlying structures. A path is cleared, and then the erupting tooth moves along it. This has clinical importance in recognizing the cause of eruption problems, particularly PFE, in which all teeth distal to the most mesial involved tooth do not erupt or respond to orthodontics. In our study of by far the largest sample of PFE cases yet reported, familial cases of PFE accounted for approximately (1/4) of all cases examined. Candidate genes now are being evaluated. In post-emergent eruption, control seems to be light forces of long duration that oppose eruption, rather than heavy forces of short duration such as those during mastication. Studies of human premolars in their passage from gingival emergence to the occlusal plane show that in this phase eruption occurs only during a few hours in the early evening. The critical hours for eruption parallel the time that growth hormone levels are highest in a growing child. In this stage intermittent force does not affect the rate of eruption, but changes in periodontal blood flow do affect it.

Genetic analysis of familial non-syndromic primary failure of eruption.

OBJECTIVES: While some eruption disorders occur as part of a medical syndrome, primary failure of eruption (PFE) - defined as a localized failure of secondary tooth eruption - exists without systemic involvement. Recent studies support that heredity may play an important role in the pathogenesis of PFE. The objective of our human genetic study is to investigate the genetic contribution to PFE. MATERIALS AND METHODS: Four candidate genes POSTN, RUNX2, AMELX, and AMBN) were investigated because of their relationship to tooth eruption or putative relationship to each other. Families and individuals were ascertained based on the clinical diagnosis of PFE. Pedigrees were constructed and analyzed by inspection to determine the mode of inheritance in four families. The candidate genes were directly sequenced for both unrelated affected individuals and unaffected individuals. A genome wide scan using 500 microsatellite markers followed by linkage analysis was carried out for one family. RESULTS: Pedigree analysis of families suggests an autosomal dominant inheritance pattern with complete penetrance and variable expressivity. Sequence analysis revealed two non-functional polymorphisms in the POSTN gene and no other sequence variations in the remaining candidate genes. Genotyping and linkage analysis of one family yielded a LOD score of 1.51 for markers D13S272; D15S118 and D17S831 on chromosomes 13, 15 and 17 respectively. CONCLUSIONS: While LOD scores were not significant evidence of linkage, extension of current pedigrees and novel SNP chip technology holds great promise for identification of a causative locus for PFE.

A novel mutation in human PAX9 causes molar oligodontia.

Experimental and animal studies, as well as genetic mutations in man, have indicated that the development of dentition is under the control of several genes. So far, mutations in MSX1 and PAX9 have been associated with dominantly inherited forms of human tooth agenesis that mainly involve posterior teeth. We identified a large kindred with several individuals affected with molar oligodontia that was transmitted as an isolated autosomal-dominant trait. Two-point linkage analysis using DNA from the family and polymorphic marker D14S288 in chromosome 14q12 produced a maximum lod score of 2.29 at theta = 0.1. Direct sequencing of exons 2 to 4 of PAX9 revealed a cytosine insertion mutation at nucleotide 793, leading to a premature termination of translation at aa 315. Our results support the conclusion that molar oligodontia is due to allelic heterogeneity in PAX9, and these data further corroborate the role of PAX9 as an important regulator of molar development.