Congenital tooth agenesis-related EDAR variants and pedigree analysis of HED patients with two variants

Abstract

Objective·To explore EDAR (ectodysplasin A receptor) gene variants that lead to congenital tooth agenesis, and preliminarily analyze the reasons why variants in EDAR can cause both syndromic and non-syndromic tooth agenesis.Methods·Patients with congenital tooth agenesis admitted to the Department of 2nd Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine and their family members were included, and genomic DNA from their peripheral blood was extracted for whole exome sequencing (WES). After preliminary screening, PolyPhen-2, Mutation Taster, and Provean were used to predict the harmfulness of potential variants. The screened variants in patients and their families were verified by Sanger sequencing. Conservation analysis of variants was performed, and Swiss-Model was used to analyze the changes in the three-dimensional structure of EDAR. The teeth and syndromic phenotype of the patients and their family members were investigated.Results·Among the included congenital tooth agenesis patients, five patients with EDAR mutations were found, one with EDAR frameshift mutation c.368_369insC(p.L123fs) and the other four with EDAR missense mutations. Two of these four patients were diagnosed as non-syndromic tooth agenesis (NSTA), resulted from c.77C>A(p.A26E) homozygous mutation and c.380C>T(p.P127L) heterozygous mutation, respectively. The other two patients with two variants were diagnosed as hypohidrotic ectodermal dysplasia (HED). One compound heterozygous missense mutation patient carried EDAR c.77C>T(p.A26V) from her father and EDAR c.1281G>C (p.L427F) from her mother; the other patient with both EDAR and EDA mutations carried EDAR c.1138A>C(p.S380R) heterozygous mutation and EDA c.1013C>T(p.T338M) hemizygous mutation. Both variants were from his mother and were reported to be related with NSTA. Two of these missense mutations, EDAR c.1281G>C(p.L427F) and EDAR c.77C>A (p.A26E), had not been reported before. The missense mutations affected the protein's spatial conformation by altering the polarity, charge, or volume of the amino acid residues. The frameshift mutation caused a non-triplet base addition, which probably led to protein truncation or degradation.Conclusion·Two new EDAR missense mutations are discovered. An NSTA patients with EDAR homozygous mutations and an HED patient with both EDA and EDAR mutations are reported. It expands the understanding of pathogenic mechanisms of EDAR mutations causing HED and NSTA.

Keywords

• ectodermal dysplasia
• familial tooth agenesis
• ectodysplasin a receptor
• ectodysplasin a
• whole exome sequencing