Novel mutations identified in patients with tooth agenesis by whole-exome sequencing

Oral Dis. 2019 Mar;25(2):523-534. doi: 10.1111/odi.13002. Epub 2018 Dec 7.

Abstract

Objectives: To identify potentially pathogenic mutations for tooth agenesis by whole-exome sequencing.

Subjects and methods: Ten Chinese families including five families with ectodermal dysplasia (syndromic tooth agenesis) and five families with selective tooth agenesis were included. Whole-exome sequencing was performed using genomic DNA. Potentially pathogenic mutations were identified after data filtering and screening. The pathogenicity of novel variants was investigated by segregation analysis, in silico analysis, and functional studies.

Results: One novel mutation (c.441_442insACTCT) and three reported mutations (c.252delT, c.463C>T, and c.1013C>T) in EDA were identified in families with ectodermal dysplasia. The novel EDA mutation was co-segregated with phenotype. A functional study revealed that NF-κB activation was compromised by the identified mutations. The secretion of active EDA was also compromised detection by western blotting. Novel Wnt10A mutations (c.521T>C and c.653T>G) and EVC2 mutation (c.1472C>T) were identified in families with selective tooth agenesis. The Wnt10A c.521T>C mutation and the EVC2 c.1472C>T mutation were considered as pathogenic for affecting highly conserved amino acids, co-segregated with phenotype and predicted to be disease-causing by SIFT and PolyPhen2. Moreover, several reported mutations in PAX9, Wnt10A, and FGFR3 were also detected.

Conclusions: Our study expanded our knowledge on tooth agenesis spectrum by identifying novel variants.

Keywords: NF-κB pathway; craniofacial anomalies; ectodermal dysplasia; oligodontia; tooth development.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anodontia / genetics*
  • Asian People / genetics
  • China
  • Ectodermal Dysplasia / genetics*
  • Ectodysplasins / genetics*
  • Ectodysplasins / metabolism
  • Exome Sequencing
  • Female
  • Frameshift Mutation
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Middle Aged
  • NF-kappa B / metabolism
  • PAX9 Transcription Factor / genetics
  • Phenotype
  • Proteins / genetics*
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Signal Transduction / genetics
  • Transfection
  • Wnt Proteins / genetics*
  • Young Adult

Substances

  • EDA protein, human
  • EVC2 protein, human
  • Ectodysplasins
  • Intercellular Signaling Peptides and Proteins
  • NF-kappa B
  • PAX9 Transcription Factor
  • PAX9 protein, human
  • Proteins
  • WNT10A protein, human
  • Wnt Proteins
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3