Abstract

Primary failure of tooth eruption (PFE) is a rare odontogenic defect and is characterized by failure of eruption of one or more permanent teeth. The aim of the study is to identify the genetic defect in a family with seven affected individuals segregating autosomal dominant non-syndromic PFE. Whole genome single-nucleotide polymorphism (SNP) genotyping was performed. SNP genotypes were analysed by DominantMapper and multiple shared haplotypes were detected on different chromosomes. Four individuals, including three affected, were exome sequenced. Variants were annotated and data were analysed while considering candidate chromosomal regions. Initial analysis of variants obtained by whole exome sequencing identified damaging variants in C15orf40, EPB41L4A, TMEM232, KMT2C, and FBXW10 genes. Sanger sequencing of all family members confirmed segregation of splice acceptor site variant (c.1013-2 A > G) in the KMT2C gene with the phenotype. KMT2C is considered as a potential candidate gene based on segregation analysis, the absence of variant in the variation databases, the presence of variant in the shared identical by descent (IBD) region and in silico pathogenicity prediction. KMT2C is a histone methyltransferase and recently the role of another member of this family (KMT2D) has been implicated in tooth development. Moreover, protein structures of KMT2C and KMT2D are highly similar. In conclusion, we have identified that the KMT2C gene mutation causes familial non-syndromic PFE. These findings suggest the involvement of KMT2C in the physiological eruption of permanent teeth.

Highlights

  • Primary failure of tooth eruption (PFE) is a rare odontogenic defect and is characterized by failure of eruption of one or more permanent teeth

  • Wingless-type MMTV integration site family (Wnt), bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), Sonic Hedgehog (Shh), parathyroid hormone (PTH) and ectodysplasin (Eda) pathways play a fundamental role during various stages of tooth development and eruption[1]

  • In order to understand the underlying molecular and genetic mechanisms, clinical examination and a detailed molecular genetic analysis were performed for all available individuals

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Summary

Introduction

Primary failure of tooth eruption (PFE) is a rare odontogenic defect and is characterized by failure of eruption of one or more permanent teeth. The aim of the study is to identify the genetic defect in a family with seven affected individuals segregating autosomal dominant non-syndromic PFE. We have identified that the KMT2C gene mutation causes familial non-syndromic PFE. These findings suggest the involvement of KMT2C in the physiological eruption of permanent teeth. Primary failure of tooth eruption (PFE) (MIM 125350) is a rare autosomal, non-syndromic disorder with complete cessation of the eruption of teeth and growth deficiency of the alveolar process in the affected region[5,6]. Detailed clinical and molecular genetic analysis were performed and a potentially pathogenic mutation was identified in KMT2C gene as an underlying cause of PFE in this family

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