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

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.

Overactivation of the NF‐κB pathway impairs molar enamel formation

“…It is therefore likely that the Eda/Edar cascade regulates another signaling pathway to control the formation and the number of molar teeth, rather than the NF‐κB pathway. Furthermore, many mutations in EDA/ERAD have been shown to cause missing teeth in humans (Clauss et al., 2008, Bergendal, 2014, Zeng et al, 2015, Liu et al., 2018, Zhao et al, 2018). We could not exclude the possibility that the function of EDA/EDAR/EDARADD/NF‐κB pathway in mice is slightly different from that in humans to control the number of teeth.…”

“…Hypohidrotic ectodermal dysplasia patients show dental abnormalities, such as hypodontia, anodontia, malformed teeth, including cone‐ or peg‐shaped teeth, and dental caries (Clauss et al., 2008, Bergendal, 2014, Zeng et al, 2015, Liu, Wang, Qin, Sun, & Zhu, 2018, Zhao et al, 2019). It is likely that dental caries is caused by enamel defects or salivary gland malfunction.…”

Functional Analysis of Ectodysplasin-A Mutations in X-Linked Non-Syndromic Hypodontia and Possible Involvement of X-Chromosome Inactivation

“…Indeed, previous investigations into the impact of syndrome-causing EDA mutations have shown that most syndrome-causing EDA mutations are predicted to cause an elimination of receptor signaling ultimately. However, some observations have indicated that an EDA mutation in a family with X-linked recessive, non-syndromic tooth agenesis, seems to be found that expression, receptor binding and signaling capability of the mutant EDA1 proteins were only impaired, rather than abolished [12][13].…”

Functional analysis of ectodysplasin-A mutations and involvement of X-chromosome inactivation

“…Indeed, previous investigations on the impact of syndrome-causing EDA mutations have shown that most syndrome-causing EDA mutations are predicted to ultimately cause receptor signalling to be eliminated. However, some observations of an EDA mutation in a family with Xlinked, recessive, non-syndromic tooth agenesis seem to indicate that the expression, receptor binding and signalling capability of the mutant EDA1 proteins were only impaired rather than abolished [13][14][15].…”