Abstract
The OTOA gene (Locus: DFNB22) is reported to be one of the causative genes for non-syndromic autosomal recessive hearing loss. The copy number variations (CNVs) identified in this gene are also known to cause hearing loss, but have not been identified in Japanese patients with hearing loss. Furthermore, the clinical features of OTOA-associated hearing loss have not yet been clarified. In this study, we performed CNV analyses of a large Japanese hearing loss cohort, and identified CNVs in 234 of 2262 (10.3%, 234/2262) patients with autosomal recessive hearing loss. Among the identified CNVs, OTOA gene-related CNVs were the second most frequent (0.6%, 14/2262). Among the 14 cases, 2 individuals carried OTOA homozygous deletions, 4 carried heterozygous deletions with single nucleotide variants (SNVs) in another allele. Additionally, 1 individual with homozygous SNVs in the OTOA gene was also identified. Finally, we identified 7 probands with OTOA-associated hearing loss, so that its prevalence in Japanese patients with autosomal recessive hearing loss was calculated to be 0.3% (7/2262). As novel clinical features identified in this study, the audiometric configurations of patients with OTOA-associated hearing loss were found to be mid-frequency. This is the first study focused on the detailed clinical features of hearing loss caused by this gene mutation and/or gene deletion.
Highlights
Hereditary hearing loss affects approximately one in 500–600 infants in developed countries, and genetic causes account for at least 50% of all childhood hearing loss [1]
We developed amplicon libraries, using an Ion AmpliSeqTM Custom Panel (ThermoFisher Scientific, Waltham, MA, USA), for 68 genes previously reported as genetic causes of non-syndromic hearing loss (Supplementary Table S1), and performed emulsion PCR and sequencing, in line with the manufacturer’s instructions
Of 2262 cases, copy number variations (CNVs) in the 68 target genes were detected in 234 cases (10.3%, 234/2262)
Summary
Hereditary hearing loss affects approximately one in 500–600 infants in developed countries, and genetic causes account for at least 50% of all childhood hearing loss [1]. Next-generation sequencing (NGS) analysis has become a powerful tool for finding variants in many rare genes, and has allowed genetic epidemiology to be clarified [3,4]. We have recently reported a series of studies on various relatively rare genes in the Japanese population, including POU4F3 [5], WFS1 [6], OTOF [7], and STRC [8]. Most of the causal mutations in these genes are small insertions/deletions (indels) or single nucleotide variants (SNVs). Copy number variations (CNVs), that is, the alteration through deletion, insertion and/or duplication of more than 1 kbp, involving the genes associated with hearing loss have been observed in several patients with hearing loss (HL) [8,9].
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