Mutations in EDA and EDAR genes cause dominant syndromic tooth agenesis

Hypohidrotic ectodermal dysplasia (HED) is a rare congenital disorder but the most common form of ectodermal dysplasia. It is characterized by an abnormal development of ectodermal-derived structures, which results in defects in skin appendages. The main signs of this disorder include abnormal or missing teeth, reduced ability of eccrine sweat glands and sparse hair. Some additional features that may be associated with HED include prominent thick lips, rings under the eyes, a pointed chin, an everted nose, frontal bossing and the sporadic absence of nipple.

HED is mainly associated with mutations in ectodysplasin A (EDA), EDA receptor (EDAR) and EDAR-associated death domain (EDARADD) which play an important role in the development of ectodermal-derived structures. Different modes of inheritance have been observed in HED, according to the gene involved but the most frequent form of this disease is the X-linked EDA-related HED.

In a new Italian study by Dr. Francesca Andreoni, Dr. Daniela Bencardino and Prof. Mauro Magnani from the University of Urbino together with Dr. Claudia Sgattoni and Dr. Oriana Simonetti from the Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona, and Prof. Antonino Forabosco from the Genomic Research Centre, Cante di Montevecchio Association, they  examined two children with clinical manifestations of HED and their parents. The results revealed  a novel variant and confirmed a previously described variant of HED and determined their inheritance mode and clinical significance. This work is published by the Journal of Molecular Genetics & Genomic Medicine.

In the first family (A), the child (proband) was a 30-month-old female born at term by induced childbirth due to oligoamnios. Clinical examination showed that she had nail dysplasia of the big toes at the base, conical mandibular teeth, absence of lateral incisors, a lower right auricle, frontal bossing, brittle hair and eutrophic skin. She had a family history of a failure of tooth development, early baldness and fragile nails with normal sweating.

In the second family (B), the child (proband) was a 28-month-old male, born at term via cesarean section due to a breech position following a normal pregnancy. He had conical teeth, mild bilateral dysplasia of the first toe, a tendency for ocular convergence, the absence of both maxillary and mandibular deciduous lateral incisors, and retractile testicles. In addition, the skin of his lower limbs appeared slightly dry and his hair was thin. A diagnosis of HED had been reported in his maternal lineage.

Following the sequencing of EDA, EDAR and EDARADD, the authors discovered a new missense variant within the EDAR in the proband of Family A. They also found that the mother of the female proband carried this variant, whereas the father was wild-type. The inheritance mode for this variant was observed to be autosomal dominant, with a destabilizing effect on the protein structure stability and binding with the ligand. The sequencing in Family B revealed a genetic variant in EDA, present in the male proband and his mother but was not found in his father, which had been described by previous studies, confirming its role in X-linked HED. The team also observed that the inheritance model of the novel mutation displayed a different relationship with X-linked HED and non-syndromic tooth agenesis. Although HED is a recessive X-linked syndrome, oligodontia manifests itself as a dominant trait characterized by incomplete penetrance in heterozygous females.

Through this study, Dr. Francesca Andreoni and colleagues reported a new mutation in EDAR and provided evidence of its pathogenicity and involvement in HED. These findings highlighted the relationship between the inheritance mode and observable traits of the identified variants. Moreover, the results of this study will be useful for genetic counselling.