Novel missense mutations in the tumor necrosis factor domain of Ectodysplasin-A cause non-syndromic tooth agenesis in two Chinese families.

OBJECTIVE

Mutations of the Ectodysplasin-A (EDA) gene are generally associated with syndromic tooth agenesis, yet their influence on non-syndromic tooth agenesis (NSTA) has not been thoroughly elucidated. This study aimed to investigate the genetic basis of NSTA and to identify pathogenic EDA mutations in two Chinese families using whole-exome sequencing, and explore the underlying mechanisms involved.

DESIGN

Two unrelated individuals with NSTA and their families were enrolled in this study, and genomic DNA was extracted from peripheral blood samples. Whole-exome sequencing was performed, followed by variants detection and filtering to identify pathogenic genes and mutations. The identified genetic mutations were further validated by Sanger sequencing and confirmed to be absent in 300 unrelated healthy individuals. Conservation analysis, three-dimensional (3D) modeling, and electrostatic potential calculations were conducted accordingly.

RESULTS

We identified a novel mutation c.827 G>T (p.Arg276Leu) and a previously reported mutation c.1069 C>T (p.Arg357Trp) in the EDA gene, with the latter showing previously unreported phenotypic characteristics. Both mutations are located in the tumor necrosis factor (TNF) domain of EDA, which is crucial for binding with ectodysplasin A receptor (EDAR). Conservation analysis indicated that these mutations are evolutionarily conserved across various species. In silico predictions and 3D modeling analyses suggested that these mutations may be pathogenic, potentially due to alterations in the hydrogen bonding and electrostatic potential, thereby affecting EDA-EDAR interaction.

CONCLUSIONS

Our findings broaden the mutation spectrum of EDA gene associated with NSTA by identifying a novel mutation and provide a basis for future genetic counseling.