Novel EDA or EDAR Mutations Identified in Patients with X-Linked Hypohidrotic Ectodermal Dysplasia or Non-Syndromic Tooth Agenesis

Abstract

Both X-linked hypohidrotic ectodermal dysplasia (XLHED) and non-syndromic tooth agenesis (NSTA) result in symptoms of congenital tooth loss. This study investigated genetic causes in two families with XLHED and four families with NSTA. We screened for mutations of WNT10A, EDA, EDAR, EDARADD, PAX9, MSX1, AXIN2, LRP6, and WNT10B through Sanger sequencing. Whole exome sequencing was performed for the proband of NSTA Family 4. Novel mutation c.1051G>T (p.Val351Phe) and the known mutation c.467G>A (p.Arg156His) of Ectodysplasin A (EDA) were identified in families with XLHED. Novel EDA receptor (EDAR) mutation c.73C>T (p.Arg25*), known EDA mutation c.491A>C (p.Glu164Ala), and known Wnt family member 10A (WNT10A) mutations c.511C>T (p.Arg171Cys) and c.742C>T (p.Arg248*) were identified in families with NSTA. The novel EDA and EDAR mutations were predicted as being pathogenic through bioinformatics analyses and structural modeling. Two variants of WNT10A, c.374G>A (p.Arg125Lys) and c.125A>G (p.Asn42Ser), were found in patients with NSTA. The two WNT10A variants were predicted to affect the splicing of message RNA, but minigene experiments showed normal splicing of mutated minigenes. This study uncovered the genetic foundations with respect to six families with XLHED or NSTA. We identified six mutations, of which two were novel mutations of EDA and EDAR. This is the first report of a nonsense EDAR mutation leading to NSTA.

Genetic diagnosis for X‐linked hypohidrotic ectodermal dysplasia family with a novel Ectodysplasin A gene mutation

“…This mutation found in this study has not been reported in the databases (https://www.ncbi.nlm.nih.gov/clinvar, http://www.hgmd.cf.ac.uk/ac/index.php). The Ectodysplasin‐A protein encoded by EDA gene consists of 391 amino acids and contains 3 structural domains including N‐terminal intracellular domain (1‐41 amino acids), transmembrane domain (42‐62 amino acids), and C‐terminal extracellular domain (63‐391 amino acids). In this family, the c.302_303delCC [p.Pro101HisfsX11] mutation in the proband's EDA gene induced EDA gene frame shift mutation which led to early termination of EDA gene translation because there was a termination codon TAA at the 11th codon behind the mutational site, so only 110 amino acids were translated and the 101‐110 amino acids were also mismatched.…”

A first case report of hypohidrotic ectodermal dysplasia from Oman

“…The index patient DNA was then subjected to full gene sequencing of the EDAR gene, which is associated with autosomal recessive ectodermal dysplasia, type 10B, and was found to carry the homozygous variant c.73C > T, p.Arg25Ter () in the EDAR gene. The EDAR:c.73C > T variant was reported previously in a 6‐year‐old female patient, albeit in heterozygous form and associated with autosomal dominant HED, type 10A …”

“…This is predicted to cause premature truncation of the EDAR protein and result in the complete deletion of the transmembrane and binding domains which are critical to the EDAR protein's function as a soluble ligand ectodysplasin A receptor and its signaling activity, respectively. The complete loss of protein function due to the c.73C > T mutation and the consequent effect on gene dosage is a likely explanation for why our patient with the homozygous form of this mutation exhibits a more severe clinical presentation than the previously reported patient who presented with tooth agenesis as its major clinical presentation attributed to the heterozygous form of the c.73C > T mutation …”

“…The EDAR:c.73C > T variant was reported previously in a 6-year-old female patient, albeit in heterozygous form and associated with autosomal dominant HED, type 10A. 6 The c.73C > T, p.Arg25Ter in the EDAR gene, creates a stop codon within exon 3 of the coding region. This is predicted to cause premature truncation of the EDAR protein and result in the complete deletion of the transmembrane and binding domains which are critical to the EDAR protein's function as a soluble ligand ectodysplasin A receptor and its signaling activity, respectively.…”

“…The complete loss of protein function due to the c.73C > T mutation and the consequent effect on gene dosage is a likely explanation for why our patient with the homozygous form of this mutation exhibits a more severe clinical presentation than the previously reported patient who presented with tooth agenesis as its major clinical presentation attributed to the heterozygous form of the c.73C > T mutation. 6 Screening for the c.73C > T mutation in the parents and normal sibling of the index patient using exon 3-specific Sanger sequencing indicated that all of them were heterozygous carriers of this mutation (Figure 2). These observations further implicated the pathogenic role of the EDAR gene: c.73C > T variant in the HED phenotype of our index patient.…”