Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis

J Dent Res. 2018 Jan;97(1):49-59. doi: 10.1177/0022034517724149. Epub 2017 Aug 16.

Abstract

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

Keywords: WNT signaling pathway; array genotyping; gene; hypodontia; next generation sequencing; oligodontia.

MeSH terms

  • Anodontia / genetics*
  • Female
  • Genetic Linkage / genetics
  • Genetic Variation / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Laminin / genetics
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics
  • Male
  • Membrane Proteins / genetics
  • Mutation, Missense / genetics
  • Pedigree
  • Real-Time Polymerase Chain Reaction
  • Turkey
  • Whole Exome Sequencing / methods
  • Wnt Proteins / genetics

Substances

  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • KREMEN1 protein, human
  • LRP6 protein, human
  • Laminin
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Membrane Proteins
  • WNT10A protein, human
  • Wnt Proteins
  • laminin alpha 3