EDA – Tooth Agenesis

EDA encodes ectodysplasin-A, a TNF family ligand essential for ectodermal appendage development. Variants in EDA can manifest as isolated tooth agenesis (MONDO:0005486), often through X-linked inheritance, affecting receptor binding and downstream NF-κB signaling.

Genetic evidence for EDA in tooth agenesis includes a novel missense mutation c.779T>G (p.Ile260Ser) identified in a Chinese family with non-syndromic hypodontia ([PMID:23625373]). Another recurrent variant, c.956G>T (p.Ser319Ile), was found in an Indian pedigree with congenital tooth agenesis and segregated in all affected individuals ([PMID:25203534]). Further, eight distinct missense variants were reported in Chinese families, all co-segregating with tooth agenesis phenotypes ([PMID:38287639]). A cohort study of 131 probands using whole-exome sequencing highlighted EDA as the most common gene in syndromic tooth agenesis patients, accounting for 24 affected individuals ([PMID:36071541]). Collectively, over 35 unrelated probands across multiple families support a strong genetic association.

The variant spectrum in EDA includes predominantly missense changes within the TNF homology domain (e.g., p.Gly291Arg, p.Thr338Met, p.Gln358Arg, p.Leu56Pro), as well as frameshift and splice site mutations in syndromic cases. These variants cluster in functionally critical regions, often altering residue solvent accessibility and receptor binding interfaces.

Functional assays demonstrate that tooth agenesis-causing EDA mutants retain partial expression but exhibit reduced binding to EDAR and compromised NF-κB activation, contrasting with syndrome-causing alleles that abolish signaling entirely ([PMID:19623212], [PMID:27144394]). Structural modeling and in vitro pull-down assays confirm impaired trimerization and receptor interaction for TNF domain variants, correlating with tooth development defects.

No conflicting evidence has been reported weakening the link between EDA variants and non-syndromic tooth agenesis. The concordance of genetic segregation and functional impairment across independent studies underpins a strong gene–disease validity.

In summary, X-linked EDA variants, particularly missense changes in the TNF homology domain, are definitively associated with tooth agenesis through haploinsufficiency and impaired NF-κB signaling. Clinically, EDA sequencing should be prioritized in male and sporadic tooth agenesis cases, guiding genetic counseling and prenatal diagnosis.

References

• Journal of dental research • 2013 • Novel EDA p.Ile260Ser mutation linked to non-syndromic hypodontia. PMID:23625373
• PloS one • 2014 • Whole genome sequencing reveals novel non-synonymous mutation in ectodysplasin A (EDA) associated with non-syndromic X-linked dominant congenital tooth agenesis. PMID:25203534
• Oral diseases • 2024 • Eight EDA mutations in Chinese patients with tooth agenesis and genotype-phenotype analysis. PMID:38287639
• Clinical genetics • 2022 • Expanding the genetic spectrum of tooth agenesis using whole-exome sequencing. PMID:36071541
• European journal of human genetics : EJHG • 2010 • Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis. PMID:19623212
• PloS one • 2016 • Functional Study of Ectodysplasin-A Mutations Causing Non-Syndromic Tooth Agenesis. PMID:27144394

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