EYA4

Chr 6AD

EYA transcriptional coactivator and phosphatase 4

Also known as: CMD1J, DFNA10

NCBI Gene: 2070ENSG00000112319UniProt: O95677

This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may act as a transcriptional activator through its protein phosphatase activity, and it may be important for eye development, and for continued function of the mature organ of Corti. Mutations in this gene are associated with postlingual, progressive, autosomal dominant hearing loss at the deafness, autosomal dominant non-syndromic sensorineural 10 locus. The encoded protein is also a putative oncogene that mediates DNA repair, apoptosis, and innate immunity following DNA damage, cellular damage, and viral attack. Defects in this gene are also associated with dilated cardiomyopathy 1J. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

Primary Disease Associations & Inheritance

?Cardiomyopathy, dilated, 1JMIM #605362
AD
Deafness, autosomal dominant 10MIM #601316
AD
585
ClinVar variants
52
Pathogenic / LP
0.05
pLI score
0
Active trials
Clinical Summary— EYA4
🧬
Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.
📋
ClinVar Variants
52 Pathogenic / Likely Pathogenic· 333 VUS of 585 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.45LOEUF
pLI 0.049
Z-score 4.18
OE 0.27 (0.16–0.45)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.12Z-score
OE missense 0.83 (0.75–0.92)
276 obs / 333.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.27 (0.16–0.45)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.75–0.92)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.84
0≤1.21.6
LoF obs/exp: 10 / 37.7Missense obs/exp: 276 / 333.4Syn Z: 1.38

ClinVar Variant Classifications

585 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic10
VUS333
Likely Benign171
Benign12
Conflicting17
42
Pathogenic
10
Likely Pathogenic
333
VUS
171
Likely Benign
12
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
1
25
0
42
Likely Pathogenic
7
0
3
0
10
VUS
4
265
57
7
333
Likely Benign
1
3
74
93
171
Benign
0
0
12
0
12
Conflicting
—17
Total28269171100585

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

EYA4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

EYA4-related dilated cardiomyopathy

limited
ADUndeterminedUncertain
Cardiac
G2P ↗

EYA4-related deafness

definitive
ADLoss Of FunctionAbsent Gene Product
Ear
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Cardiomyopathy, dilated, 1J

MIM #605362

Molecular basis of disorder known

Autosomal dominant

Deafness, autosomal dominant 10

MIM #601316

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — EYA4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic etiology of non-syndromic hearing loss in Europe.
Del Castillo I et al.·Hum Genet
2022Review
Genetic analysis of patients with low-frequency non-syndromic hearing loss.
Yu S et al.·Mol Genet Genomics
2024Cohort
Prevalence and clinical features of hearing loss caused by EYA4 variants.
Shinagawa J et al.·Sci Rep
2020Clinical trial
EYA4 promotes breast cancer progression and metastasis through its role in replication stress avoidance.
de la Peña Avalos B et al.·Mol Cancer
2023
Global Distribution of Founder Variants Associated with Non-Syndromic Hearing Impairment.
Aboagye ET et al.·Genes (Basel)
2023Review
Identification of a novel EYA4 likely pathogenic variant in a Chinese family with postlingual non-syndromic hearing loss and analysis of molecular epidemiology of EYA4 variants.
Xue J et al.·BMC Med Genomics
2024Case report
Eya4 Induces Hypertrophy via Regulation of p27kip1.
Williams T et al.·Circ Cardiovasc Genet
2015
Aberrant methylation of EYA4 promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma.
Luo M et al.·Cancer Sci
2018
EYA4 inhibits hepatocellular carcinoma growth and invasion by suppressing NF-κB-dependent RAP1 transactivation.
Mo SJ et al.·Cancer Commun (Lond)
2018
DFNA10/EYA4--the clinical picture.
De Leenheer EM et al.·Adv Otorhinolaryngol
2002
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools