EDA – Hypohidrotic Ectodermal Dysplasia

X-linked hypohidrotic ectodermal dysplasia (HED; MONDO:0016535) is characterized by sparse hair, reduced sweat gland function, and hypodontia, and is caused predominantly by pathogenic variants in EDA (HGNC:3157). EDA encodes ectodysplasin-A, a TNF-family ligand required for activation of NF-κB via its receptor EDAR in ectodermal appendage development ([PMID:11279189]).

Genetic evidence for EDA involvement is definitive: mutations in EDA have been identified in over 100 unrelated XLHED families, with hemizygous variants segregating in affected males and heterozygous carriage in females ([PMID:11295832]; [PMID:27305980]). In one series, five affected males in a multi-generation pedigree exhibited the classic triad of HED, with carrier females demonstrating mosaic sweat-gland function ([PMID:22421994]).

EDA variants span the spectrum from missense and nonsense to splice-site and frameshift changes. Recurrent hemizygous missense mutations such as c.466C>T (p.Arg156Cys) disrupt the conserved TNF homology domain and abrogate receptor binding ([PMID:11295832]; [PMID:11279189]). Loss-of-function alleles—including frameshifts and splice-donor mutations—prevent proper multimerization or proteolytic release of soluble ectodysplasin-A ([PMID:11295832]; [PMID:11416205]).

Functional studies demonstrate that disease-causing EDA mutants fail to activate NF-κB and reduce downstream transcription of ectodermal differentiation genes. In vitro assays show impaired EDAR binding and diminished NF-κB reporter activation for both missense and truncating variants ([PMID:11279189]; [PMID:19623212]). These data confirm a haploinsufficiency mechanism in X-linked HED.

There is no significant conflicting evidence: autosomal forms of HED due to EDAR or EDARADD mutations phenocopy XLHED but are clinically indistinguishable, underscoring the central role of EDA–EDAR signaling ([PMID:10677098]).

In summary, EDA meets ClinGen’s Definitive criteria for XLHED based on extensive case and functional data. Genetic testing for EDA variants enables accurate diagnosis, carrier detection, prenatal counseling, and potential targeted therapeutic development.

Key Take-home: EDA mutations cause X-linked HED via loss of ectodysplasin-A function and NF-κB signaling, supporting its utility in clinical diagnostics and genetic counseling.

References

• Human molecular genetics • 1998 • The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats. PMID:9736768
• The Journal of biological chemistry • 2001 • Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A. PMID:11279189
• Human mutation • 2001 • The mutation spectrum of the EDA gene in X-linked anhidrotic ectodermal dysplasia. PMID:11295832
• Journal of human genetics • 2016 • Mutational spectrum in 101 patients with hypohidrotic ectodermal dysplasia and breakpoint mapping in independent cases of rare genomic rearrangements. PMID:27305980
• European journal of human genetics • 2010 • Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis. PMID:19623212

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