Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss

Abstract

The genetic heterogeneity of sensorineural hearing loss (SNHL) is a major hurdle to the detection of disease-causing variants. We aimed to identify underlying causal genes associated with mid-frequency hearing loss (HL), which contributes to less than about 1% of SNHL cases, by whole exome sequencing (WES). Thirty families segregating mid-frequency SNHL, in whom biallelic GJB2 mutations had been previously excluded, were selected from among 851 families in our DNA repository of SNHL. DNA samples from the probands were subjected to WES analysis and searched for candidate variants associated with SNHL. We were able to identify the genetic aetiology in six probands (20%). In total, we found three pathogenic and three likely pathogenic variants in four genes (COL4A5, OTOGL, TECTA, TMPRSS3). One more proband was a compound heterozygote for a pathogenic variant and a variant of uncertain significance (VUS) in MYO15A gene. To date, MYO15A and TMPRSS3 have not yet been described in association with mid-frequency SNHL. In eight additional probands, eight candidate VUS variants were detected in five genes (DIAPH1, MYO7A, TECTA, TMC1, TSPEAR). Seven of these 16 variants have not yet been published or mentioned in the available databases. The most prevalent gene was TECTA, identified in 23% of all tested families. Furthermore, we confirmed the hypothesis that a substantive portion of cases with this conspicuous audiogram shape is a consequence of a genetic disorder.

A Novel Variant in the DIAPH1 Gene Causing Macrothrombocytopenia and Non-syndromic Hearing Loss in a Pediatric Saudi Girl

“…Hearing loss associated with DIAPH1 typically begins in the low-frequency region. It progresses throughout the entire frequency range, starting in the first 10 years of life and advancing rapidly to a profound degree by the fourth decade [ 12 , 13 ]. While non-syndromic hearing loss is usually not accompanied by other clinical appearances, certain autosomal dominant loci, such as autosomal dominant non-syndromic hearing loss 1 (DFNA1), may present with additional signs like thrombocytopenia [ 14 , 15 ].…”

The genomic landscape of Ménière's disease: a path to endolymphatic hydrops

“…Prioritizing MD-related mutated genes by inclusion of biological interaction networks to 481 genes points to MPHOSPH8 associated with transcriptional suppression, MYO18A associated with hair cell–cell junction proteins [ 41 ], TRIOBP associated with human deafness and essential for thickening bundles of F-actin in rootlets, establishing their mature dimensions and for stiffening supporting cells of the auditory sensory epithelium [ 42 ], and OTOGL associated with vertigo [ 43 ] and midfrequency hearing loss [ 44 ], as key MD genes. In addition, disruptions in genes instrumental to otic capsule and temporal bone development may lead to sensorineural hearing loss, dizziness, and vertigo; key symptoms of MD [ 45 ].…”

Role of Cytoskeletal Diaphanous-Related Formins in Hearing Loss

“…The following are available online at , Table S1: Pathogenic mutations in DRF genes associated with a hearing phenotype; Table S2: Pathogenic mutations in DRF genes associated with diseases that do not include a hearing phenotype [ 71 , 72 , 73 , 74 , 75 , 76 , 77 ].…”