Genotype-Phenotype Correlations of Pathogenic COCH Variants in DFNA9: A HuGE Systematic Review and Audiometric Meta-Analysis

Robijn, Sybren M. M.; Smits, Jeroen J.; Sezer, Kadriye; Huygen, P.L.M.; Beynon, Andy J.; Wijk, Erwin van; Kremer, Hannie; Vrieze, Erik de; Lanting, Cornelis P.; Pennings, Ronald J.E.

doi:10.3390/biom12020220

Cited by 8 publications

(8 citation statements)

References 74 publications

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“…These findings may help clinicians to prescribe treatment plans to delay or stop the progression of hearing loss. The genotype–phenotype relationship of TBC1D24 patients is not clear, and similar mutations may lead to various phenotypic differences, which is also common in other gene mutation studies 43 . Because non-syndromic hearing loss has no obvious external phenotype, such as physical defects, it is difficult to infer the mutation location in the genotype by phenotype.…”

Section: Discussionmentioning

confidence: 99%

Investigation of a novel TBC1D24 variation causing autosomal dominant non-syndromic hearing loss

Lei,

Zhu,

Dong

2024

Sci Rep

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Hearing loss is considered one of the most common sensory neurological defects, with approximately 60% of cases attributed to genetic factors. Human pathogenic variants in the TBC1D24 gene are associated with various clinical phenotypes, including dominant nonsyndromic hearing loss DFNA65, characterized by progressive hearing loss after the development of language. This study provides an in-depth analysis of the causative gene and mutations in a family with hereditary deafness. We recruited a three-generation family with autosomal dominant nonsyndromic hearing loss (ADNSHL) and conducted detailed medical histories and relevant examinations. Next-generation sequencing (NGS) was used to identify genetic variants in the proband, which were then validated using Sanger sequencing. Multiple computational software tools were employed to predict the impact of the variant on the function and structure of the TBC1D24 protein. A series of bioinformatics tools were applied to determine the conservation characteristics of the sequence, establish a three-dimensional structural model, and investigate changes in molecular dynamics. A detailed genotype and phenotype analysis were carried out. The family exhibited autosomal dominant, progressive, postlingual, and nonsyndromic sensorineural hearing loss. A novel heterozygous variant, c.1459C>T (p.His487Tyr), in the TBC1D24 gene was identified and confirmed to be associated with the hearing loss phenotype in this family. Conservation analysis revealed high conservation of the amino acid affected by this variant across different species. The mutant protein showed alterations in thermodynamic stability, elasticity, and conformational dynamics. Molecular dynamics simulations indicated changes in RMSD, RMSF, Rg, and SASA of the mutant structure. We computed the onset age of non-syndromic hearing loss associated with mutations in the TBC1D24 gene and identified variations in the hearing progression time and annual threshold deterioration across different frequencies. The identification of a new variant associated with rare autosomal dominant nonsyndromic hereditary hearing loss in this family broadens the range of mutations in the TBC1D24 gene. This variant has the potential to influence the interaction between the TLDc domain and TBC domain, thereby affecting the protein’s biological function.

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Section: Discussionmentioning

confidence: 99%

Investigation of a novel TBC1D24 variation causing autosomal dominant non-syndromic hearing loss

Lei,

Zhu,

Dong

2024

Sci Rep

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“…The Usher2a and non–ocular Stickler groups comprised members from different families with different pathogenic causative variants. This may be important as the auditory phenotype may vary substantially with the specific variant found [ 44 , 45 ]. Even within families where siblings share the same pathogenic variant and environment, the phenotype may vary considerably [ 46 ], indicating that modulating variables, such as modifying genes, epigenetics, and environmental factors may cause differences.…”

Section: Discussionmentioning

confidence: 99%

Genetic Hearing Loss Affects Cochlear Processing

Lanting¹,

Snik²,

Leijendeckers³

et al. 2022

Genes

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The relationship between speech recognition and hereditary hearing loss is not straightforward. Underlying genetic defects might determine an impaired cochlear processing of sound. We obtained data from nine groups of patients with a specific type of genetic hearing loss. For each group, the affected cochlear site-of-lesion was determined based on previously published animal studies. Retrospectively obtained speech recognition scores in noise were related to several aspects of supra-threshold cochlear processing as assessed by psychophysical measurements. The differences in speech perception in noise between these patient groups could be explained by these factors and partially by the hypothesized affected structure of the cochlea, suggesting that speech recognition in noise was associated with a genetics-related malfunctioning of the cochlea. In particular, regression models indicate that loudness growth and spectral resolution best describe the cochlear distortions and are thus a good biomarker for speech understanding in noise.

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“…COCH is the causal gene for DFNA9, characterized by a progressive high-frequency SNHL with variable progressive vestibular impairment [ 39 ]; however, a family was reported in South Korea with episodic vertigo and bilateral SNHL with the mutation p.Cys162Tyr was considered a MD-like phenotype [ 40 ]. In the adult mouse cochlea, Cochlin is also a protein expressed in the fibrocytes of spiral ligament and spiral limbus, but not in the organ of Corti or the stria vascularis.…”

Section: Types Of Inheritance and Genes In MDmentioning

confidence: 99%

Types of Inheritance and Genes Associated with Familial Meniere Disease

Parra-Perez

Lopez-Escamez

2023

JARO

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Meniere disease (MD) is a rare disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. The phenotype is variable, and it may be associated with other comorbidities such as migraine, respiratory allergies, and several autoimmune disorders. The condition has a significant heritability according to epidemiological and familial segregation studies. Familial MD is found in 10% of cases, the most frequently found genes being OTOG, MYO7A, and TECTA, previously associated with autosomal dominant and recessive non-syndromic SNHL. These findings suggest a new hypothesis where proteins involved in the extracellular structures in the apical surface of sensory epithelia (otolithic and tectorial membranes) and proteins in the stereocilia links would be key elements in the pathophysiology of MD. The ionic homeostasis of the otolithic and tectorial membranes could be critical to suppress the innate motility of individual hair cell bundles. Initially, focal detachment of these extracellular membranes may cause random depolarization of hair cells and will explain changes in tinnitus loudness or trigger vertigo attacks in early stages of MD. With the progression of the disease, a larger detachment will lead to an otolithic membrane herniation into the horizontal semicircular canal with dissociation in caloric and head impulse responses. Familial MD shows different types of inheritance, including autosomal dominant and compound recessive patterns and implementation of genetic testing will improve our understanding of the genetic structure of MD.

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Genotype-Phenotype Correlations of Pathogenic COCH Variants in DFNA9: A HuGE Systematic Review and Audiometric Meta-Analysis

Cited by 8 publications

References 74 publications

Investigation of a novel TBC1D24 variation causing autosomal dominant non-syndromic hearing loss

Investigation of a novel TBC1D24 variation causing autosomal dominant non-syndromic hearing loss

Genetic Hearing Loss Affects Cochlear Processing

Types of Inheritance and Genes Associated with Familial Meniere Disease

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