• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
EDA (HGNC:3157) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
ectodysplasin A
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
ED1, EDA2, ODT1
Alias symbols
EDA1, XLHED, HED, XHED, ED1-A1, ED1-A2, EDA-A1, EDA-A2
%HI
2.43(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.97(Read more about gnomAD pLI score)
LOEUF
0.27(Read more about gnomAD LOEUF score)
Cytoband
Xq13.1
Genomic Coordinates
GRCh37/hg19: chrX:68835957-69259322 NCBI Ensembl UCSC
GRCh38/hg38: chrX:69616113-70039472 NCBI Ensembl UCSC
MANE Select Transcript
NM_001399.5 ENST00000374552.9 (Read more about MANE Select)
Function
Cytokine which is involved in epithelial-mesenchymal signaling during morphogenesis of ectodermal organs. Functions as a ligand activating the DEATH-domain containing receptors EDAR and EDA2R (PubMed:8696334, PubMed:11039935, PubMed:27144394, PubMed:34582123). May also play a role in cell adhesion (By similarity). {ECO:0000250|UniProtKB:O54693, ECO:0000269|PubMed:11039935, ECO:0000269|PubMed:27144394, ECO:0000269|PubMed:34582123, ECO:0000269|PubMed:8696334}. [Isoform 1]: Binds only to the recept... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-16110
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
01/25/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • X-linked hypohidrotic ectodermal dysplasia Monarch
HI Evidence:
  • PUBMED: 18510547
    Lexner et al. (2008) presented a series of 67 patients from 19 families (24 affected males and 43 carrier females). All participants had clinical signs of hypohidrotic ectodermal dysplasia (HED) and a disease causing EDA variant. The EDA gene was screened for pathogenic variants by SSCP and direct sequencing. MLPA analysis was used to detect deletions and duplications in female probands. Sixteen different variants were detected in 19 families: 7 missense (Families 1-9), 3 frameshift (Families 11,12,13), 4 large deletions of one or more exons (Families 14-17) note: family 16 and 17 had the same variant, 2 splice site variants (Families 18 and 19), 1 in-frame deletion (Family 10). None of these variants were previously described, and all were predicted to either produce a truncated protein or no protein. MLPA analysis identified Family 14 with a heterozygous deletion of exon 1 in a female proband and her affected mother. Both females presented with pronounced symptoms and predominantly inactivated normal X allele.
  • PUBMED: 17568423
    Orstavik et al. (2007) describe a female with HED as severe as a males with XLHED. X inactivation studies showed a complete skewed pattern with the paternal X as the active X chromosome. Sequencing of the EDA gene showed no variants. Whole chromosome paint revealed a de novo insertion. FISH analysis showed at least a 4 Mb portion of the X chromosome containing XIST was inserted into 9p13 in conjunction with a de novo pericentric inversion of chromosome 9. The proximal breakpoint of the inserted portion of the X chromosome was within the EDA gene and the distal breakpoint was determined to be distal to the XIST gene. It was determined that because the XIST gene was lacking on the X chromosome with the disrupted EDA gene, the normal X was inactivated.
  • PUBMED: 9683615
    Monreal et al 1998, identified isolated an EDA isoform (alternative transcript-isoform II) and is expected to represent the major EDA transcript. Authors also screened for variants in affected males with classic XLHED from 18 unrelated families. Families D1018, ED1097 were identified with de novo intragenic deletions resulting in frameshift and premature stop. Family ED1001 had a base pair substitution resulting in a premature stop (familial testing is unclear).
  • PUBMED: 18666859
    Conte et al. (2008) performed DHPLC analysis of the EDA gene in 23 Italian patients with HED. Eighteen variants (14 novel, 4 recurrent) were identified in males with classic XLHED . None of the variants were seen in 100 unaffected males. 8 missense variants 3 in-frame deletions 1 nonsense variant (unknown inheritance) 1 intragenic deletion 4 splice variants (2 maternal carriers, 2 unknown inheritance) 1 synonymous variant
  • PUBMED: 21457804
    Zhang et al. (2011) looked at pathogenic variants in the EDA gene and XLHED vs non-syndromic hypodontia (NSH). Authors screened the EDA gene in 27 non-consanguineous Chinese XLHED subjects and looked at the genotype (EDA mutation site and inheritance pattern) and phenotype correlation of these two conditions and reviewed previously published published data on NSH subjects. Seventeen EDA variants were identified in 20 non-consanguineous subjects: 4 deletions, 1 insertion, and 2 nonsense were predicted to lead to premature termination of protein translation. A 648-665 del18 variant was predicted to result in the formation of a protein lacking six amino acids. The remaining 9 variants were missense. The mothers of 13 subjects were EDA variant carriers. Genotype/phenotype analysis was based on the present study and data of NSH subjects collected previously. The variants observed in NSH subjects were mainly missense whereas only half of the XLHED were missense. Non-missense variants resulted in more severe phenotype.
HI Evidence Comments:
Loss of function variants in EDA cause X-linked hypohidrotic ectodermal dysplasia (XLHED). Many types of variants have been described, including nonsense, frameshift, and exonic deletions, and are catalogued in the LOVD database. Males have a classic clinical presentations and females may present with milder clinical features. Females with XLHED show mosaic patterns of sweat pore function and distribution. Females with XLHED may present with mild HED and may exhibit any or all cardinal features of XLHED (See GeneReviews). Additional supporting publications for LOF include Zhang et al 2008 (PMID 18702659), Lin et al 2004 (PMID:15347342), Chao et al, 2003 (PMID:12923595). Al Marzouqi et al. (2014) (PMID: 24689965) also describe a female with typical HED (sparse scalp hair, lack of sweating, hypodontia and mucous membrane dryness) and bilateral amastia. A de novo duplication of exon 2 was identified by MLPA. X-inactivation studies in leukocytes showed inactivation skewed (11% vs 89%).
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)