EDARADD

Chr 1ADAR

EDAR associated via death domain

Also known as: CR, ECTD11A, ECTD11B, ED3, EDA3

NCBI Gene: 128178 ENSG00000186197 UniProt: Q8WWZ3 OMIM: 606603

The protein functions as an adapter that couples the EDAR receptor to downstream NF-kappa-B signaling pathways during morphogenesis of ectodermal organs including hair follicles, teeth, and sweat glands. Mutations cause ectodermal dysplasia affecting hair, teeth, and sweat gland development, with both autosomal dominant and autosomal recessive inheritance patterns described. The gene shows low constraint against loss-of-function variants (pLI 0.0003, LOEUF 1.15), consistent with recessive disease mechanisms being possible.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene was identified by its association with ectodermal dysplasia, a genetic disorder characterized by defective development of hair, teeth, and eccrine sweat glands. The protein encoded by this gene is a death domain-containing protein, and is found to interact with EDAR, a death domain receptor known to be required for the development of hair, teeth and other ectodermal derivatives. This protein and EDAR are coexpressed in epithelial cells during the formation of hair follicles and teeth. Through its interaction with EDAR, this protein acts as an adaptor, and links the receptor to downstream signaling pathways. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 1.152 OMIM phenotypes

Clinical Summary— EDARADD

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.000

Z-score 1.21

OE 0.61 (0.35–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.14Z-score

OE missense 0.72 (0.60–0.85)

91 obs / 127.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.35–1.15)

0≤0.351.4

Missense OE?0.72 (0.60–0.85)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 7 / 11.4Missense obs/exp: 91 / 127.3Syn Z: 0.11

This gene — mechanism propensity

0.6064th %ile

GOF

0.7125th %ile

LOF

0.2679th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNNuclear factor (NF)-kB reporter assays demonstrated that all the mutant EDARADD showed reduction in activation of NF-?B. Importantly, p.D120Y-, p.L122R-, and p.D123N-mutant EDARADD slightly reduced the NF-kB activity induced by wild-type EDARADD in a dominant negative manner.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References