RESUMO
OBJECTIVE: Eyes absent 4 (EYA4) is the causative gene of autosomal dominant non-syndromic hereditary hearing loss, DFNA10. We aimed to identify a copy number variation of EYA4 in a non-syndromic sensory neural hearing loss pedigree. FAMILY AND CLINICAL EVALUATION: A Japanese family showing late-onset and progressive hearing loss was evaluated. A pattern of autosomal dominant inheritance of hearing loss was recognized in the pedigree. No cardiac disease was observed in any of the individuals. METHODS: Targeted exon sequencing was performed using massively parallel DNA sequencing (MPS) analysis. Scanning of the array comparative genomic hybridization (aCGH) was completed and the copy number variation (CNV) data from the aCGH analysis was confirmed by matching all CNV calls with MPS analysis. Breakpoint detection was performed by whole-genome sequencing and direct sequencing. Sequencing results were examined, and co-segregation analysis of hearing loss was completed. RESULTS: We identified a novel hemizygous indel that showed CNV in the EYA4 gene from the position 133,457,057 to 133,469,892 on chromosome 6 (build GRCh38/hg38) predicted as p.(Val124_Pro323del), and that was segregated with post-lingual and progressive autosomal dominant sensorineural hearing loss by aCGH analysis. CONCLUSION: Based on the theory of genotype-phenotype correlation with EYA4 mutations in terms of hearing loss and comorbid dilated cardiomyopathy, the region of amino acids 124 to 343 is hypothesized not to be the pathogenic region causing dilated cardiomyopathy. Additionally, the theory of genotype-phenotype correlation about the prevalence of dilated cardiomyopathy is thought to be rejected because of no correlation of deleted amino acid region with the prevalence of dilated cardiomyopathy. These results will help expand the research on both the coordination of cochlear transcriptional regulation and normal cardiac gene regulation via EYA4 transcripts and provide information on the genotype-phenotype correlations of DFNA10 hearing loss.