Early truncation of the N-terminal variable region of EYA4 gene causes dominant hearing loss without cardiac phenotype

Background: Autosomal dominant hearing loss (ADHL) accounts for about 20% of all hereditary non-syndromic HL. Truncating mutations of the EYA4 gene can cause either non-syndromic ADHL or syndromic ADHL with cardiac abnormalities. It has been proposed that truncations of the C-terminal Eya domain lead to non-syndromic HL, whereas early truncations of the N-terminal variable region cause syndromic HL with cardiac phenotype.

Methods: The proband and all the other hearing impaired members of the family underwent a thorough clinical and audiological evaluation. The cardiac phenotype was examined by ECG and echocardiography. Their DNA was subjected to target exome sequencing of 129 known deafness genes. The sequencing data were analyzed and the candidate variants were interpreted following the ACMG guidelines for clinical sequence interpretation. The effect of candidate variant on EYA4 gene expression was assessed by quantitative PCR and western blot of gene production in blood.

Results: We report a Chinese family cosegregating post-lingual onset, progressive ADHL with a novel nonsense mutation NM_004100.4:c.543C>G (p.Tyr181Ter) of EYA4. Two affected members show no cardiac abnormalities at least until now revealed by electrocardiography and echocardiography. The overall expression level of the EYA4 gene in the proband was lower than that in his unaffected relative.

Conclusion: This report expands the mutational spectrum of the EYA4 gene and highlights the fact that more data are needed to elucidate the complex genotype-phenotype correlation of EYA4 mutations.