A novel nonsense PTH1R variant shows incomplete penetrance of primary failure of eruption: a case report

Background: Aim of this work was to describe a rare inheritance pattern of Primary Failure of Eruption (PFE) in a small family with incomplete penetrance of PFE and a novel nonsense PTH1R variant. Case presentation: The proband, a 26 year-old man with a significant bilateral open-bite, was diagnosed with PFE using clinical and radiographic characteristics. DNA was extracted from the proband and his immediate family using buccal swabs and the entire PTH1R coding sequence was analyzed, revealing a novel heterozygous nonsense variant in exon 7 of PTH1R (c.505G > T). This variant introduces a premature stop codon in position 169, predicted to result in the production of a truncated and non-functional protein. This variant has never been reported in association with PFE and is not present in the Genome Aggregation Database (gnomAD). Interestingly, the c.505G > T variant has also been identified in the unaffected mother of our proband, suggesting incomplete penetrance of PFE. Conclusions: In this study, we report a new PTH1R variant that segregates in an autosomal dominant pattern and causes PFE with incomplete penetrance. This underlines the diagnostic value of a thorough clinical and genetic analysis of all family members in order to estimate accurate recurrence risks, identify subtle clinical manifestations and provide proper management of PFE patients

Simultaneous sequencing of oxidized methylcytosines produced by TET/JBP dioxygenases in Coprinopsis cinerea

A prominent epigenetic mechanism for gene regulation is methylation of cytosine bases in DNA. TET enzymes facilitate DNA demethylation by converting 5-methylcytosine (5mC) to oxidized methylcytosines (oxi-mCs). We show that oxi-mCs are generated by conserved TET/JBP enzymes encoded in the genome of the model organism Coprinopsis cinerea and present a method for simultaneous mapping of the three different species of oxi-mCs at near–base-pair resolution. We observe that centromeres and transposable elements exhibit distinctive patterns of 5mC and oxi-mC, and show that gene body 5mC and oxi-mC mark silent paralogous multicopy genes. Our study describes a method to map three species of oxi-mC simultaneously and reveals the colocation of 5mC and oxi-mC at functional elements throughout the C. cinerea genome

Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis.

Mutations of the Ectodysplasin-A (EDA) gene are generally associated with the syndrome hypohidrotic ectodermal dysplasia (MIM 305100), but they can also manifest as selective, non-syndromic tooth agenesis (MIM300606). We have performed an in vitro functional analysis of six selective tooth agenesis-causing EDA mutations (one novel and five known) that are located in the C-terminal tumor necrosis factor homology domain of the protein. Our study reveals that expression, receptor binding or signaling capability of the mutant EDA1 proteins is only impaired in contrast to syndrome-causing mutations, which we have previously shown to abolish EDA1 expression, receptor binding or signaling. Our results support a model in which the development of the human dentition, especially of anterior teeth, requires the highest level of EDA-receptor signaling, whereas other ectodermal appendages, including posterior teeth, have less stringent requirements and form normally in response to EDA mutations with reduced activity

Primary failure of eruption: Clinical and genetic findings in the mixed dentition

ABSTRACT Objective: To test the hypothesis that mutations in the parathyroid hormone 1 receptor (PTH1R) include effects in both primary and permanent teeth. Materials and Methods: DNA was extracted from saliva samples of 29 patients (8 familial and 21 sporadic) who presented with clinical evidence of infraoccluded teeth, and their unaffected relatives (N \ubc 22). Sequencing followed by mutational analysis of the coding regions of PTH1R gene was completed for all individuals (N \ubc 29). Results: Eight of 29 cases revealed a heterozygous pathogenic variant in the PTH1R gene; five of eight variants represented distinct mutations based on comparison with the dbSNP, HGMD, and ESP databases. One mutation (c.1765 T.C p.Trp89Arg) was found to segregate within a family (n \ubc3). In silico analyses for all variants revealed a putative pathogenic effect. A genotype-phenotype correlation was reported as defined by a functional mutation in PTH1R and corresponding effects on one or more posterior teeth only; unilateral or bilateral involvement, infraoccluded primary teeth. Conclusions: Novel mutations were reported in the PTH1R gene that included PFE-affected primary molars, thus providing the basis for using a genetic diagnostic tool for early diagnosis leading to proper management

Primary Failure of Eruption: Clinical and Genetic Findings in the Mixed Dentition

CONTROL ID: 2639647 TITLE: Primary Failure of Eruption: Clinical and Genetic Findings in the Mixed Dentition AUTHORS (FIRST NAME INITIAL LAST NAME): C. Grippaudo1, I. D'Apolito1, C. Cafiero1, B. Ricci1, S. A. Frazier- Bowers2 AUTHORS/INSTITUTIONS: C. Grippaudo, I. D'Apolito, C. Cafiero, B. Ricci, Dental Institute, Universit\ue0 Cattolica, Rome, ITALY|S.A. Frazier-Bowers, Department of Orthodontics, University of North Carolina, Chapel Hill, North Carolina, UNITED STATES| PREFERRED PRESENTATION TYPE: Oral CURRENT SCIENTIFIC GROUPS & NETWORKS: Craniofacial Biology ABSTRACT BODY: Objectives: Eruption disorders represent an enigmatic aspect of dental and orthodontic diagnosis. Since the discovery that Primary Failure of Eruption (PFE, MIM #125350) is due to a genetic defect, several mutations of the PTH1R gene have been identified as causative. This study aimed to refine our understanding of the phenotype:genotype correlation of PFE and PTH1R mutations in the mixed dentition. This characterization may lead to improved diagnostic approaches and provide the foundation for downstream mechanistic studies to understand the pathogenesis of PTH1R mutations. Methods: DNA was extracted from saliva samples of 29 patients (3 families and 23 unrelated individuals) who presented with clinical evidence of infraoccluded teeth. Mutational analysis was completed for the coding regions of PTH1R gene following PCR amplification and direct sequencing. Results: Eight of 29 cases revealed a heterozygous pathogenic variant in the PTH1R gene; 5 of 8 variants represent distinct mutations within the cohort. One mutation (c.1765 T>C p.Trp89Arg) was found to segregate within a family (n=3) represented by two generations. Mutational analysis using the dbSNP, HGMD and the ESP databases identified the mutations were previously unreported. In silico analyses of all variants further predicted a putative pathogenic effect. Extended clinical analysis of the cohrot verified that all the novel mutations co-segregated with the PFE phenotype that included affection of the mixed dentition. Six of the 8 patients carrying a functional PTH1R mutation were children in mixed dentition with one or more primary teeth affected. Conclusions: We report that PFE in the mixed and permanent dentition positively correlates with pathogenic mutations in the PTH1R gene. Further studies to identify additional genes and correlate the pathogenesis of PFE from mixed to permanent dentition are ongoing and forthcoming. (no table selected) TABLE FOOTER: (No Tables) (No Image Selected) KEYWORDS: Primary failure of eruption (PFE), orthodontics, Dental eruption, genetics, mixed dention. Support Funding Agency/Grant Number - Abstracts: Financial Interest Disclosure: NONE AWARDS: Group Author Abstracts - Abstract: Session Chair Volunteers - Abstracts: Not Interested Special Scheduling Needs - Abstracts: Student Status - Abstracts: No Student Other Designation - Abstracts: Abstract Submission - Track Selection: Clinician Trac

Orthognathic speech pathology: impacts of Class III malocclusion on speech

Introduction: Patients with dentofacial disharmonies (DFDs) seek orthodontic care and orthognathic surgery to address issues with mastication, esthetics, and speech. Speech distortions are seen 18 times more frequently in Class III DFD patients than the general population, with unclear causality. We hypothesize there are significant differences in spectral properties of stop (/t/ or /k/), fricative (/s/ or /ʃ/), and affricate (/tʃ/) consonants and that severity of Class III disharmony correlates with the degree of speech abnormality. Methods: To understand how jaw disharmonies influence speech, orthodontic records and audio recordings were collected from Class III surgical candidates and reference subjects (n = 102 Class III, 62 controls). A speech pathologist evaluated subjects and recordings were quantitatively analysed by Spectral Moment Analysis for frequency distortions. Results: A majority of Class III subjects exhibit speech distortions. A significant increase in the centroid frequency (M1) and spectral spread (M2) was seen in several consonants of Class III subjects compared to controls. Using regression analysis, correlations between Class III skeletal severity (assessed by cephalometric measures) and spectral distortion were found for /t/ and /k/ phones. Conclusions: Class III DFD patients have a higher prevalence of articulation errors and significant spectral distortions in consonants relative to controls. This is the first demonstration that severity of malocclusion is quantitatively correlated with the degree of speech distortion for consonants, suggesting causation. These findings offer insight into the complex relationship between craniofacial structures and speech distortions

Simultaneous sequencing of oxidized methylcytosines produced by TET/JBP dioxygenases in Coprinopsis cinerea

TET/JBP enzymes oxidize 5-methylpyrimidines in DNA. In mammals, the oxidized methylcytosines (oxi-mCs) function as epigenetic marks and likely intermediates in DNA demethylation. Here we present a method based on diglucosylation of 5-hydroxymethylcytosine (5hmC) to simultaneously map 5hmC, 5-formylcytosine, and 5-carboxylcytosine at near–base-pair resolution. We have used the method to map the distribution of oxi-mC across the genome of Coprinopsis cinerea, a basidiomycete that encodes 47 TET/JBP paralogs in a previously unidentified class of DNA transposons. Like 5-methylcytosine residues from which they are derived, oxi-mC modifications are enriched at centromeres, TET/JBP transposons, and multicopy paralogous genes that are not expressed, but rarely mark genes whose expression changes between two developmental stages. Our study provides evidence for the emergence of an epigenetic regulatory system through recruitment of selfish elements in a eukaryotic lineage, and describes a method to map all three different species of oxi-mCs simultaneously