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

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.

Abstract

In this study, two families with clinical manifestations of hypohidrotic ectodermal dysplasia (HED) were investigated. The novel missense variant NM_022336.4:c.287T>C (p.Phe96Ser) in EDAR was identified in family A. This finding strongly suggests that the EDAR mutation in exon 4 is the cause of the disease with autosomal dominant inheritance because of its phenotypic manifestation also in heterozygosity and family segregation. 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. 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.