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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.

SUBMITTER: Pavlenkova Z

PROVIDER: S-EPMC8602250 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To date, 102 genes have been reported as responsible for non-syndromic hearing loss, some of which are associated with specific audiogram features. Four genes have been reported as causative for mid-frequency sensorineural hearing loss (MFSNHL), among which TECTA is the most frequently reported; however, the prevalence of TECTA mutations is unknown. To elucidate the prevalence of TECTA mutation in MFSNHL and clarify genotype-phenotype correlations, we analyzed the genetic and clinical features of patients with MFSNHL.Subjects with bilateral non-syndromic hearing loss were prescreened for GJB2 and m.1555A > G and m.3243A > G mitochondrial DNA mutations, and patients with inner ear malformations were excluded. We selected MFSNHL patients whose audiograms met the U-shaped criterion proposed by the GENDEAF study group, along with those with shallow U-shaped audiograms, for TECTA analysis. All TECTA exons were analyzed by Sanger sequencing. Novel missense variants were classified as possibly pathogenic, non-pathogenic, and variants of uncertain significance, based on genetic data. To evaluate novel possibly pathogenic variants, we predicted changes in protein structure by molecular modeling.Pathogenic and possibly pathogenic variants of TECTA were found in 4 (6.0%) of 67 patients with MFSNHL. In patients with U-shaped audiograms, none (0%) of 21 had pathogenic or possibly pathogenic variants. In patients with shallow U-shaped audiograms, four (8.7%) of 46 had pathogenic or possibly pathogenic variants. Two novel possibly pathogenic variants were identified and two previously reported mutations were considered as variant of unknown significance. The clinical features of patients with pathogenic and possibly pathogenic variants were consistent with those in previous studies. Pathogenic or possibly pathogenic variants were identified in 3 of 23 families (13.0%) which have the family histories compatible with autosomal dominant and 1 of 44 families (2.3%) which have the family histories compatible with sporadic or autosomal recessive.TECTA mutations were identified in 6.0% of MFSNHL. These mutations were more frequent in patients with shallow U-shaped audiograms than those with U-shaped audiograms, and in families which have the family histories compatible with autosomal dominant than those with the family histories compatible with sporadic or autosomal recessive.

Project description:IntroductionTo compare inpatient treated patients with idiopathic (ISSNHL) and non-idiopathic sudden sensorineural hearing loss (NISSNHL) regarding frequency, hearing loss, treatment and outcome.MethodsAll 574 inpatient patients (51% male, median age: 60 years) with ISSNHL and NISSNHL, who were treated in federal state Thuringia in 2011 and 2012, were included retrospectively. Univariate and multivariate statistical analyses were performed.ResultsISSNHL was diagnosed in 490 patients (85%), NISSNHL in 84 patients (15%). 49% of these cases had hearing loss due to acute otitis media, 37% through varicella-zoster infection or Lyme disease, 10% through Menière disease and 7% due to other reasons. Patients with ISSNHL and NISSNHL showed no difference between age, gender, side of hearing loss, presence of tinnitus or vertigo and their comorbidities. 45% of patients with ISSNHL and 62% with NISSNHL had an outpatient treatment prior to inpatient treatment (p < 0.001). The mean interval between onset of hearing loss to inpatient treatment was shorter in ISSNHL (7.7 days) than in NISSNHL (8.9 days; p = 0.02). The initial hearing loss of the three most affected frequencies in pure-tone average (3PTAmax) scaled 72.9 dBHL ± 31.3 dBHL in ISSNHL and 67.4 dBHL ± 30.5 dBHL in NISSNHL. In the case of acute otitis media, 3PTAmax (59.7 dBHL ± 24.6 dBHL) was lower than in the case of varicella-zoster infection or Lyme disease (80.11 dBHL ± 34.19 dBHL; p = 0.015). Mean absolute hearing gain (Δ3PTAmaxabs) was 8.1 dB ± 18.8 dB in patients with ISSNHL, and not different in NISSNHL patients with 10.2 dB ± 17.6 dB. A Δ3PTAmaxabs ≥ 10 dB was reached in 34.3% of the patients with ISSNHL and to a significantly higher rate of 48.8% in NISSNHL patients (p = 0.011).ConclusionsISSNHL and NISSNHL show no relevant baseline differences. ISSNHL tends to have a higher initial hearing loss. NISSHNL shows a better outcome than ISSNHL.

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

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