Patterns of missing teeth in a population of oligodontia patients

Purpose: The purpose of this study was to characterize a population of oligodontia patients and identify patterns of tooth agenesis. Materials and Methods: A total of 116 patients with nonsyndromic oligodontia were studied, and the Tooth Agenesis Code (TAC) per quadrant was calculated. Oligodontia was defined as the congenital absence of 6 or more permanent teeth, excluding the third molars. The TAC is a unique number, consistent with a specific pattern of tooth agenesis. The authors suggest the use of an overall TAC with which the dentition throughout the mouth can be presented by a single number. Frequency analysis was used to study the prevalence of various patterns. Results: There was a great diversity of TACs. In the maxilla, agenesis of both premolars and the lateral incisor or the presence of only the central incisor and first molar were the most common patterns. In the mandible, agenesis of the second premolar or both premolars occurred most frequently, Conclusions: No single pattern of agenesis occurred more than twice when the full mouth was viewed. Hence, the presentation of the dentition in oligodontia is very heterogeneous. Evaluation of treatment strategies in oligodontia patients is a methodologic challenge because homogenous, comparable subgroups of patients are not available

Loss-of-Function Mutations in the WNT Co-receptor LRP6 Cause Autosomal-Dominant Oligodontia

Tooth agenesis is one of the most common developmental anomalies in man. Oligodontia, a severe form of tooth agenesis, occurs both as an isolated anomaly and as a syndromal feature. We performed exome sequencing on 20 unrelated individuals with apparent non-syndromic oligodontia and failed to detect mutations in genes previously associated with oligodontia. In three of the probands, we detected heterozygous variants in LRP6, and sequencing of additional oligodontia-affected individuals yielded one additional mutation in LRP6. Three mutations (c.1144_1145dupAG [p.Ala383Glyfs*8], c.1779dupT [p.Glu594*], and c.2224_2225dupTT [p.Leu742Phefs*7]) are predicted to truncate the protein, whereas the fourth (c.56C>T [p.Ala19Val]) is a missense variant of a conserved residue located at the cleavage site of the protein's signal peptide. All four affected individuals harboring a LRP6 mutation had a family history of tooth agenesis. LRP6 encodes a transmembrane cell-surface protein that functions as a co-receptor with members from the Frizzled protein family in the canonical Wnt/β-catenin signaling cascade. In this same pathway, WNT10A was recently identified as a major contributor in the etiology of non-syndromic oligodontia. We show that the LRP6 missense variant (c.56C>T) results in altered glycosylation and improper subcellular localization of the protein, resulting in abrogated activation of the Wnt pathway. Our results identify LRP6 variants as contributing to the etiology of non-syndromic autosomal-dominant oligodontia and suggest that this gene is a candidate for screening in DNA diagnostics

Compound heterozygous NEK1 variants in two siblings with oral-facial-digital syndrome type II (Mohr syndrome)

The oral-facial-digital (OFD) syndromes comprise a group of related disorders with a combination of oral, facial and digital anomalies. Variants in several ciliary genes have been associated with subtypes of OFD syndrome, yet in most OFD patients the underlying cause remains unknown. We investigated the molecular basis of disease in two brothers with OFD type II, Mohr syndrome, by performing single-nucleotide polymorphism (SNP)-array analysis on the brothers and their healthy parents to identify homozygous regions and candidate genes. Subsequently, we performed whole-exome sequencing (WES) on the family. Using WES, we identified compound heterozygous variants c.[464G>C];[1226G>A] in NIMA (Never in Mitosis Gene A)-Related Kinase 1 (NEK1). The novel variant c.464G>C disturbs normal splicing in an essential region of the kinase domain. The nonsense variant c.1226G>A, p.(Trp409*), results in nonsense-associated alternative splicing, removing the first coiled-coil domain of NEK1. Candidate variants were confirmed with Sanger sequencing and alternative splicing assessed with cDNA analysis. Immunocytochemistry was used to assess cilia number and length. Patient-derived fibroblasts showed severely reduced ciliation compared with control fibroblasts (18.0 vs 48.9%, P<0.0001), but showed no significant difference in cilia length. In conclusion, we identified compound heterozygous deleterious variants in NEK1 in two brothers with Mohr syndrome. Ciliation in patient fibroblasts is drastically reduced, consistent with a ciliary defect pathogenesis. Our results establish NEK1 variants involved in the etiology of a subset of patients with OFD syndrome type II and support the consideration of including (routine) NEK1 analysis in patients suspected of OFD.European Journal of Human Genetics advance online publication, 17 August 2016; doi:10.1038/ejhg.2016.103

Compound heterozygous NEK1 variants in two siblings with oral-facial-digital syndrome type II (Mohr syndrome)

The oral-facial-digital (OFD) syndromes comprise a group of related disorders with a combination of oral, facial and digital anomalies. Variants in several ciliary genes have been associated with subtypes of OFD syndrome, yet in most OFD patients the underlying cause remains unknown. We investigated the molecular basis of disease in two brothers with OFD type II, Mohr syndrome, by performing single-nucleotide polymorphism (SNP)-array analysis on the brothers and their healthy parents to identify homozygous regions and candidate genes. Subsequently, we performed whole-exome sequencing (WES) on the family. Using WES, we identified compound heterozygous variants c.[464G>C];[1226G>A] in NIMA (Never in Mitosis Gene A)-Related Kinase 1 (NEK1). The novel variant c.464G>C disturbs normal splicing in an essential region of the kinase domain. The nonsense variant c.1226G>A, p.(Trp409*), results in nonsense-associated alternative splicing, removing the first coiled-coil domain of NEK1. Candidate variants were confirmed with Sanger sequencing and alternative splicing assessed with cDNA analysis. Immunocytochemistry was used to assess cilia number and length. Patient-derived fibroblasts showed severely reduced ciliation compared with control fibroblasts (18.0 vs 48.9%, P<0.0001), but showed no significant difference in cilia length. In conclusion, we identified compound heterozygous deleterious variants in NEK1 in two brothers with Mohr syndrome. Ciliation in patient fibroblasts is drastically reduced, consistent with a ciliary defect pathogenesis. Our results establish NEK1 variants involved in the etiology of a subset of patients with OFD syndrome type II and support the consideration of including (routine) NEK1 analysis in patients suspected of OFD

Dentofacial characteristics of patients with hypodontia

Item does not contain fulltextThis study aims to identify distinctive dentofacial characteristics of hypodontia patients. For this purpose, 189 young hypodontia patients (cases) were divided into subgroups, based on criteria from literature. Normalised differences between cases and controls were calculated for various parameters of dentofacial form. Subsequently, cluster analysis was applied to disclose subsets of hypodontia patients with distinctive dentofacial features. The ANB angle, interincisal angle and lower anterior face height were consistently significantly different amongst the subsets. Four clusters of patients with an increasing number of missing teeth and distinctive dentofacial characteristics could be identified. Patients in cluster 1 display a high-angle facial pattern. Patients in clusters 2 and 3 exhibit markable dentoalveolar characteristics (a relatively small and a large interincisal angle, respectively). Patients in cluster 4 exhibited notable sagittal-skeletal discriminative features predominantly because of a retrognathic maxilla. The smallest nasolabial angle and lower anterior face height were seen in this cluster. It is concluded that the anterior-posterior relationship between the jaws, the interincisal angle and the lower anterior face height are discriminative parameters of dentofacial form in hypodontia patients. Patients with hypodontia can be clustered in four groups, each with distinctive vertical-skeletal, dentoalveolar and sagittal-skeletal characteristics. This categorisation of patients with hypodontia into meaningful groups may be useful for treatment planning, interdisciplinary communication and as a means of identifying groups of patients that qualify for reimbursement of costs. Other dental factors should be appreciated as well during restorative clinical decision making in patients with hypodontia.1 augustus 201

The association between WNT10A variants and dental development in patients with isolated oligodontia

In this study we aimed to determine the effect of WNT10A variants on dental development in patients with oligodontia. Forty-three (25 boys and 18 girls) individuals were eligible for this study. Stage of development for each present tooth was assessed using the Demirjian method. In case no corresponding tooth was present, regression equations were applied for dental age to be calculated. The ratio between length of root and length of crown was ascertained for each present tooth in all quadrants. All patients were physically examined by a clinical geneticist and DNA analysis of the WNT10A gene was performed. Linear regression models were applied to analyze the association between WNT10A variants and dental age. The same analysis was applied to study the association between WNT10A variants and root elongation for each present tooth. One ordinal regression model was applied to analyze the association between WNT10A variants and development of present maxillary and mandibular teeth. Thirty-six (84%) patients were detected with WNT10A variants of which six patients displayed evident ectodermal features. Dental age was 1.50 (95% confidence interval (CI): -2.59, -0.42) to 1.96 (95% CI: -3.76, -0.17) years lower in patients with WNT10A variants compared with patients without variants. The development of maxillary canine, maxillary second molar and mandibular second molar was statistically significantly delayed in patients with WNT10A variants compared with patients without variants. The impact of WNT10A variants on dental development increases with presence of the nonsense c.(321C>A p.(C107*)) variant and the number of missing teeth