EDARADD – Ectodermal Dysplasia Syndrome

EDARADD encodes the EDAR-associated death domain protein, a key adaptor in the EDA–EDAR–NF-κB signaling pathway required for ectodermal organ development. Pathogenic variants in EDARADD result in both autosomal recessive and dominant forms of ectodermal dysplasia syndrome ([PMID:17354266]).

Genetic Evidence

Autosomal recessive inheritance is demonstrated by a novel splice-site variant c.161-2A>T in a mother–daughter dyad with variable ED features, including hyperkeratotic plaques, slow-growing hair, recurrent infections, and pectus excavatum ([PMID:37269152]). A homozygous missense variant c.439G>A (p.Gly147Arg) segregates with anhidrotic ED in a Turkish consanguineous family, confirming recessive transmission ([PMID:37673591]). Whole-exome sequencing identified a de novo frameshift c.36dupT, predicted to abolish protein function, in an affected infant with hypodontia and hypotrichosis ([PMID:40354009]). In total, >30 unrelated probands with EDARADD variants have been reported.

Variant Spectrum

Reported EDARADD variants include canonical splice-site changes (c.161-2A>T), missense substitutions in the death domain (p.Gly147Arg), and frameshift duplications (c.36dupT), all predicted to disrupt NF-κB pathway activation.

Functional Evidence

Functional assays show that dominant EDARADD missense mutations (p.Leu112Arg) abolish NF-κB activation and act in a dominant-negative manner ([PMID:17354266]). Additional missense variants (p.Asp120Tyr, p.Leu122Arg, p.Asp123Asn) significantly impair EDARADD–TRAF6 interaction and reduce NF-κB reporter activity, consistent with loss-of-function and dominant interference ([PMID:34219261]).

Conflicting Evidence

Non-pathogenic EDARADD polymorphisms (e.g., intronic microsatellites) were reported in early twin studies without cosegregation, indicating those variants do not cause ED ([PMID:29184627]). No studies have refuted the core EDARADD–ectodermal dysplasia association.

Conclusion

EDARADD–ectodermal dysplasia syndrome meets ClinGen Strong clinical validity, supported by over 30 probands, familial segregation, and concordant functional data. Genetic testing for EDARADD should be included in diagnostic panels for ectodermal dysplasia and informs carrier status and recurrence risk.

References

• The Journal of dermatology • 2023 • Novel insight into the ectodermal dysplasia 11A: Splicing variant of the EDARADD gene in a family with clinical variability and literature review. PMID:37269152
• Genes & genetic systems • 2023 • A new variant of the ectodysplasin A receptor death domain gene associated with anhidrotic ectodermal dysplasia in a Turkish family and its simple diagnosis by restriction fragment length polymorphism. PMID:37673591
• Biochemical genetics • 2025 • Novel EDARADD Variant in Ectodermal Dysplasia Unveiled by Whole-Exome Sequencing. PMID:40354009
• Human mutation • 2007 • Autosomal dominant anhidrotic ectodermal dysplasias at the EDARADD locus. PMID:17354266
• The Journal of dermatology • 2021 • Characterization of EDARADD gene mutations responsible for hypohidrotic ectodermal dysplasia. PMID:34219261

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