Genetic analysis of familial non‐syndromic primary failure of eruption

Abstract

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 due to 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 4 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 2 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.Clinical Relevance-When the process of normal tooth eruption fails, it may result in a clinically guarded or hopeless prognosis. Our studies aim to understand the etiological basis of Primary Failure of Eruption (PFE) toward the development of future orthodontic or pharmocologic interventions that will successfully treat this problem.

Primary Failure of Eruption (PFE) – Clinical and Molecular Genetics Analysis

“…In a recently-published study by Frazier-Bowers et al [11], a LOD score of 1.51 was achieved for markers D13S272, D15S118 and D17S831 on chromosomes 13, 15 and 17, respectively, in a linkage analysis of a family with PFE. However, they did not find the gene underlying this anomaly.…”

Impacted mandibular second molars

“…Recently, mutations in parathyroid hormone receptor 1 (PTH1R) have been identified in several familial cases of primary failure of eruption. 8,9 Local factors related to the failure of eruption include malocclusion disturbances of the deciduous dentition, the position of the adjacent teeth, space deficiency in the dental arch, idiopathic factors, supernumerary teeth, odontomas, or cysts. 2,4,5,7 Problems associated with impacted second molars are caries, periodontitis, resorption of adjacent teeth, cyst formation, malocclusion, and pain.…”

PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling

“…While the first reported 3 mutations (c.463G>T, c.543+1G>A, c.1050-3C>G) in patients with PFE were predicted to generate loss-of-function proteins [3], the spectrum of PTH1R mutations by now has been expanded by several investigators showing the occurrence of more than 40 potentially pathogenic mutations [4, 6–8]. Furthermore, occurrence of sporadic cases of PTH1R mutations causing PFE have been identified by exome resequencing [9].…”