GeneBe

EDARADD

protein-coding

EDAR associated via death domain

Gene summary

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]

MANE transcript

NM_145861.4

Inheritance

AR, AD, SD

ClinVar variants

P:17U:54B:9

Top phenotype

Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant; Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr1:236,348,257-236,502,915

External References & Databases

Ensembl (ENSG00000186197)NCBI Gene (128178)OMIM (606603)HGNC:14341GenCCUniProt (Q8WWZ3)AlphaFoldClinVar (EDARADD)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~154.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive hypohidrotic ectodermal dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016619

Submitter: Orphanet

tooth agenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005486

Submitter: Orphanet

autosomal dominant hypohidrotic ectodermal dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015884

Submitter: Orphanet

ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013983

Submitter: Labcorp Genetics (formerly Invitae)

ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013982

Submitter: Labcorp Genetics (formerly Invitae)

hypohidrotic ectodermal dysplasiaSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0016535

Submitter: PanelApp Australia

ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013983

Submitter: Ambry Genetics

ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominantMODERATE

Inheritance Pattern: SD

Disease ID:MONDO:0013982

Submitter: Ambry Genetics

ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominantMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013982

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant; Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessiveAD/AR

Manifestation: Dental; Dermatologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 9245989; 11780064; 17354266; 20979233; 21626677; 21876339Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EDARADD variants in ClinVar

10 Conditions Cataloged
Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessiveTotal: 37
Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominantTotal: 34
Inborn genetic diseasesTotal: 29
not providedTotal: 21
Hypohidrotic ectodermal dysplasiaTotal: 10
not specifiedTotal: 9
Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominantTotal: 3
ECTODERMAL DYSPLASIA 11B, HYPOHIDROTIC/HAIR/TOOTH TYPE, AUTOSOMAL DOMINANTTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145861.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
8
clinvar
 9
missense
4
clinvar
8
clinvar
48
clinvar
1
clinvar
 61
nonsense
2
clinvar
1
clinvar
 3
start loss
0
frameshift
2
clinvar
 2
splice donor/acceptor (+/-2bp)
2
clinvar
1
clinvar
2
clinvar
 5
Total89549080

Highest pathogenic variant AF is 0.000015755346

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_145861.4RefSeqNP_665860.26MANE Select
ENST00000334232.9EnsemblENSP00000335076.46MANE Select
NM_001422628.1RefSeqNP_001409557.15Standard
NM_080738.5RefSeqNP_542776.16Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
edaraddDanio rerio

Structure: chondrocranium cartilage

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • EDA Signalling in Hair Follicle Development
  • TNFR2 non-canonical NF-kB pathway
  • Cytokine Signaling in Immune system
  • Immune System
  • TNFs bind their physiological receptors

Biological Process

  • multicellular organism development
  • cell differentiation
  • tumor necrosis factor-mediated signaling pathway

Molecular Function

  • protein binding

Cellular Component

  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000334232
Coding exons
6
Length
136653
Individuals with no LoFs
125730
Homozygous LoFs
0
Heterozygous LoFs
18
Defined
125748
p
0.0000716
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.14911270.7150.000007211445
Missense (PolyPhen)3459.140.57491656
Synonymous0.1104647.00.9800.00000282378
Loss of Function1.21711.40.6145.78e-7132

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000790.000079rare
South Asian0.0000660.000065rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Adapter protein that interacts with EDAR DEATH domain and couples the receptor to EDA signaling pathway during morphogenesis of ectodermal organs. Mediates the activation of NF- kappa-B. {ECO:0000269|PubMed:11882293}.;
Disease
DISEASE: Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive (ECTD11B) [MIM:614941]: A disorder due to abnormal development of two or more ectodermal structures, and characterized by sparse hair (atrichosis or hypotrichosis), abnormal or missing teeth and the inability to sweat due to the absence of sweat glands. {ECO:0000269|PubMed:11780064, ECO:0000269|PubMed:17354266, ECO:0000269|PubMed:20222921}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0938

Intolerance Scores

LoFtool
0.394
RVIS EVS
0.19
RVIS percentile EVS
66.82

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.637

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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