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Case Reports
. 2021 Jan;9(1):e1555.
doi: 10.1002/mgg3.1555. Epub 2020 Nov 18.

Missense mutations in EDA and EDAR genes cause dominant syndromic tooth agenesis

Francesca Andreoni  1 , Claudia Sgattoni  2 , Daniela Bencardino  1 , Oriana Simonetti  3 , Antonino Forabosco  4 , Mauro Magnani  1
Affiliations
Case Reports

Missense mutations in EDA and EDAR genes cause dominant syndromic tooth agenesis

Francesca Andreoni et al. Mol Genet Genomic Med. 2021 Jan.

Abstract

Background: Hypohidrotic ectodermal dysplasia (HED) is the most common form of ectodermal dysplasia and is mainly associated with mutations in the EDA, EDAR, and EDARADD responsible for the development of ectodermal-derived structures. HED displays different modes of inheritance according to the gene that is involved, with X-linked EDA-related HED being the most frequent form of the disease.

Methods: Two families with tooth agenesis and manifestations of HED underwent clinical examination and EDA, EDAR, and EDARADD genetic analysis. The impact of the novel variant on the protein was evaluated through bioinformatics tools, whereas molecular modeling was used to predict the effect on the protein structure.

Results: A novel missense variant was identified in the EDAR (c.287T>C, p.Phe96Ser) of a female child proband and her mother, accounting for autosomal dominant HED. The genetic variant c.866G>A (p.Arg289His) in EDA, which has been previously described, was observed in the male proband of another family confirming its role in X-linked HED. The inheritance model of the missense mutation showed a different relationship with X-linked HED and non-syndromic tooth agenesis.

Conclusion: Our findings provide evidence of variable expression of HED in heterozygous females, which should be considered for genetic counseling, and different modes of inheritance related to tooth development.

Keywords: EDA; EDAR; ectodermal dysplasia; hypodontia.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Pedigree of family A carrying a variant in the EDAR gene. The novel mutation c.287T>C (p.Phe96Ser) was found in the EDAR gene of the proband and her mother in heterozygous form. Each of the main clinical features of HED (oligodontia, hypotrichosis, and hypohidrosis) was indicated individually, whereas sporadic and mild signs were included in “other symptoms of HED.” The black arrow points to the proband.
FIGURE 2
FIGURE 2
Pedigree of family B carrying a mutation in the EDA gene. The c.866G>A (p.Arg289His) variant was identified both in the EDA gene of the proband (hemizygote) and his mother (heterozygote). Each of the main clinical features of HED (oligodontia, hypotrichosis, and hypohidrosis) was indicated individually, whereas sporadic and mild signs were included in “other symptoms of HED”. The black arrow points to the proband.
FIGURE 3
FIGURE 3
Multiple sequence alignments of human EDAR (a) and EDA (b) with their homologs at positions 96 and 289, respectively.
FIGURE 4
FIGURE 4
Location of the mutation p.Phe96Ser of the EDAR protein in a 3D structural context visualized by Chimera 1.14. The H‐bonds and interatomic distances are shown neighboring the amino acid 96. (a) Wild‐type protein; (b) Mutated EDAR protein; (c) Wild‐type EDAR (blue) ‐ EDA (pink shades) complex.
See this image and copyright information in PMC

References

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