EDARADD – EDARADD-related Hypohidrotic Ectodermal Dysplasia

EDARADD encodes the EDAR-associated death domain protein, a critical intracellular adaptor in the ectodysplasin A receptor (EDAR)–NF-κB signaling cascade driving ectodermal organogenesis. Pathogenic variants in EDARADD underlie autosomal recessive hypohidrotic ectodermal dysplasia (HED), characterized by sparse hair, hypodontia, and reduced sweating.

Genetic evidence for EDARADD-associated HED derives from multiple unrelated cases in diverse ethnic backgrounds. One Mongolian patient harbored a novel heterozygous c.391C>T (p.Pro131Ser) variant in the death domain of EDARADD (1 proband; PMID:20477971). A Japanese kindred carried c.367G>A (p.Asp123Asn) with autosomal dominant features (1 proband; PMID:26440664). Two Turkish siblings from consanguineous parents exhibited a homozygous frameshift insertion c.322_323insCGGGC (p.Arg108ProfsTer7) (2 probands; PMID:38840186). An Iranian toddler presented with a pathogenic loss-of-function c.36dupT (p.?), confirmed by ACMG criteria (1 proband; PMID:40354009). Additionally, a homozygous in-frame deletion c.402_407del (p.Thr135_Val136del) was reported in one consanguineous family (1 proband; PMID:20222921). Segregation analysis in the Turkish family demonstrated both parents as unaffected carriers and two affected siblings (2 affected relatives; PMID:38840186).

The variant spectrum in EDARADD spans critical death-domain residues and frameshift mutations. Predominant classes include missense substitutions (c.391C>T (p.Pro131Ser); c.367G>A (p.Asp123Asn)), an insertion leading to a premature stop (c.322_323insCGGGC (p.Arg108ProfsTer7)), and in-frame deletion (c.402_407del (p.Thr135_Val136del)). A reported neutral polymorphism p.Ser93Phe highlights the importance of functional validation (PMID:18231121).

Functional assays corroborate a loss-of-function mechanism via impaired NF-κB activation and defective EDAR binding. The p.Pro131Ser and p.Asp123Asn mutants demonstrated reduced reporter activity in tissue culture ([PMID:26440664]) while c.402_407del abolished EDARADD–EDAR interaction and downstream signaling ([PMID:20222921]). Dominant variants p.Leu112Arg and p.Glu142Lys showed differential dominant-negative effects on wild-type EDARADD NF-κB activation ([PMID:17354266]).

One study identified a likely benign EDARADD p.Ser93Phe variant in an HED cohort, arguing against pathogenicity in isolation (PMID:18231121). No other large-scale studies have disputed the association, and no alternative phenotypes have been convincingly linked to EDARADD variants beyond HED.

In summary, biallelic EDARADD variants consistently impair EDAR-mediated NF-κB signaling, causing autosomal recessive hypohidrotic ectodermal dysplasia. This moderate body of genetic and functional evidence supports clinical genetic testing of EDARADD in HED cases. Key take-home: Pathogenic EDARADD mutations are a confirmed cause of autosomal recessive HED and should be included in diagnostic panels and genetic counseling.

References

• Orthodontics & craniofacial research • 2010 • A Mongolian patient with hypohidrotic ectodermal dysplasia with a novel P121S variant in EDARADD. PMID:20477971
• American journal of medical genetics. Part A • 2016 • A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia. PMID:26440664
• Italian journal of pediatrics • 2024 • Novel homozygous frameshift insertion variant in the last exon of the EDARADD causing hypohidrotic ectodermal dysplasia in two siblings: case report and review of the literature. PMID:38840186
• Biochemical genetics • 2025 • Novel EDARADD Variant in Ectodermal Dysplasia Unveiled by Whole-Exome Sequencing. PMID:40354009
• The British journal of dermatology • 2010 • Mutations in EDARADD account for a small proportion of hypohidrotic ectodermal dysplasia cases. PMID:20222921
• Human mutation • 2007 • Autosomal dominant anhidrotic ectodermal dysplasias at the EDARADD locus. PMID:17354266
• European journal of human genetics : EJHG • 2008 • Mutation screening of the Ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia. PMID:18231121

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