Mid-Frequency Hearing Loss Is Characteristic Clinical Feature of OTOA-Associated Hearing Loss

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.

The Importance of Early Genetic Diagnostics of Hearing Loss in Children

“…The pure tone audiogram curve could have a sloping, flat, rising, or mid-frequency loss (cookie bite) configuration, which is essential in genetic diagnostics of hearing loss [ 3 ]. While the sloping curve is more characteristic of acquired hearing loss [ 4 ], the cookie bite curve tends to be characteristic of genetic etiology [ 5 ]. Patients with mid-frequency loss seldom use hearing aids as their hearing at low and high frequencies is normal.…”

Enzymology and significance of protein histidine methylation

“…Few studies have yet focused on the physiological implications of METTL9 and its links to disease. However, independent genetic studies have linked chromosomal deletion of a segment encompassing METTL9, as well as the IGSF6 and OTOA genes, to colonic hypoganglionosis ( 61 ) and hearing loss ( 62 ).…”

A Missense POU4F3 Variant Associated with Autosomal Dominant Midfrequency Hearing Loss Alters Subnuclear Localization and Transcriptional Capabilities

“…OTOA encodes otoancorin, a protein that acts as a glycosylphosphatidylinositol (GPI) anchorage, and is important for limbal attachment of the tectorial membrane, which is important for conditioning proper stimulation of the inner hair cells [ 14 , 15 ]. The similarities between the clinical characteristics of hearing loss in patients with OTOA and TECTA disease-causing variants reflect the similar mechanism of hearing loss caused by tectorial membrane impairment [ 3 ]. However, the detailed underlying mechanism associated with MFSNHL remains unknown.…”

“…Midfrequency sensorineural hearing loss (MFSNHL) is a severe condition that can affect hearing and speech at an early stage. Thus far, 7 genes have been identified in relation to this condition: TECTA, OTOA, EYA4, COL11A2, CCDC50, POU4F3, and SLC44A4 [1][2][3][4][5][6][7]. Mutational analysis of these genes can be used in a clinical setting to aid in the molecular diagnosis of MFSNHL.…”