EYA4 – DFNA10 Hearing Loss

EYA4 encodes a 640–amino-acid transcriptional coactivator comprising a variable region (eya-VR) and a highly conserved Eya homologous region (eya-HR). Heterozygous mutations in EYA4 underlie autosomal dominant nonsyndromic hearing loss type 10 (DFNA10), characterized by postlingual onset and progressive sensorineural hearing loss.

EVIDENCE FROM CASE REPORTS AND SERIES:
Several cohorts have identified pathogenic EYA4 variants in DFNA10 families. In a Korean cohort of 14 families, targeted exome sequencing revealed a novel truncating variant, c.1194delT (p.Met401TrpfsTer3), in one proband that co-segregated with a down-sloping moderate hearing loss in three affected relatives and was absent in 592 controls (PMID:26015337). In a Japanese series of 1,336 autosomal dominant hearing loss families, screening of EYA4 found 12 probands (0.90%) carrying 11 novel variants and two recurrent alleles, including nonsense, frameshift, missense, splice, and copy-number losses, exemplified by c.887C>T (p.Ser296Leu) (PMID:32107406). A four-generation Chinese family harbored a novel frameshift, c.1745_1748del (p.Glu582ValfsTer6), with perfect co-segregation and a typical mid-to-high frequency down-sloping audiogram (PMID:39358765).

VARIANT SPECTRUM & INHERITANCE:
DFNA10 follows an autosomal dominant pattern. The mutational spectrum includes truncating variants (nonsense, frameshift), missense substitutions, splice-site changes, and exonic deletions. Reported variants cluster across both eya-VR and eya-HR domains, with truncating alleles generally associated with pan-frequency loss and nontruncating alleles with high-frequency predominance. Penetrance is high, with onset from adolescence to middle age and progression of ~0.63 dB/year (PMID:32107406).

FUNCTIONAL AND EXPERIMENTAL STUDIES:
Yeast two-hybrid assays demonstrated that Eya4HR interacts with Six1, albeit more weakly than Eya1HR, and that truncating mutations (e.g., R564X) abolish translation, supporting haploinsufficiency as the pathogenic mechanism (PMID:15492887). In zebrafish, eya4 knockdown recapitulates hearing and cardiac phenotypes, confirming a role in inner ear development (PMID:15735644). Cardiac‐specific transgenic mice expressing the human E193 truncation likewise develop cardiac hypertrophy and dilated cardiomyopathy, while hearing impairment parallels the human SNHL phenotype (PMID:26499333).

CONCLUSION & CLINICAL UTILITY:
The convergence of multiple unrelated DFNA10 families, consistent segregation, a broad variant spectrum, and concordant functional data supports a Strong clinical validity for EYA4 in DFNA10. Genetic testing for EYA4 variants is warranted in patients with postlingual progressive sensorineural hearing loss, guiding prognosis and family counseling.

References

• European archives of oto-rhino-laryngology • 2016 • Identification of a novel truncation mutation of EYA4 in moderate degree hearing loss by targeted exome sequencing. PMID:26015337
• Scientific Reports • 2020 • Prevalence and clinical features of hearing loss caused by EYA4 variants. PMID:32107406
• BMC Medical Genomics • 2024 • 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. PMID:39358765
• Journal of the Association for Research in Otolaryngology • 2004 • A comparative study of Eya1 and Eya4 protein function and its implication in branchio-oto-renal syndrome and DFNA10. PMID:15492887
• Nature Genetics • 2005 • Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. PMID:15735644
• Circulation. Cardiovascular Genetics • 2015 • Eya4 Induces Hypertrophy via Regulation of p27kip1. PMID:26499333

Evidence Based Scoring (AI generated)