Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University.
Department of Otorhinolaryngology, Shinshu University School of Medicine.
Otol Neurotol. 2021 Aug 1;42(7):e866-e874. doi: 10.1097/MAO.0000000000003169.
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.
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.
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.
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.
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.
眼睛缺失 4 （EYA4）是常染色体显性非综合征遗传性听力损失，DFNA10 的致病基因。我们旨在鉴定一个非综合征感觉神经性听力损失家系中 EYA4 的拷贝数变异。
对一个表现为迟发性和进行性听力损失的日本家系进行了评估。该家系中识别出听力损失的常染色体显性遗传模式。在任何个体中均未观察到心脏疾病。
使用大规模平行 DNA 测序（MPS）分析进行靶向外显子测序。完成了阵列比较基因组杂交（aCGH）的扫描，并通过将所有 CNV 调用与 MPS 分析匹配来确认 aCGH 分析的拷贝数变异（CNV）数据。通过全基因组测序和直接测序进行断点检测。检查测序结果，并完成听力损失的共分离分析。
我们在染色体 6 上 EYA4 基因的位置 133,457,057 到 133,469,892 处发现了一个新的杂合缺失，显示出 CNV（构建体 GRCh38/hg38）预测为 p.（Val124_Pro323del），该缺失与 aCGH 分析中的后天性和进行性常染色体显性感觉神经性听力损失共分离。
基于 EYA4 突变与听力损失和合并扩张型心肌病的基因型-表型相关性理论，氨基酸 124 到 343 区域被假设不是引起扩张型心肌病的致病区域。此外，由于缺失氨基酸区域与扩张型心肌病的流行率之间没有相关性，因此认为扩张型心肌病流行率的基因型-表型相关性理论被拒绝。这些结果将有助于扩大对 EYA4 转录物协调耳蜗转录调节和正常心脏基因调节的研究，并提供关于 DFNA10 听力损失的基因型-表型相关性的信息。
