Genetic Load of Alternations of Transcription Factor Genes in Non-Syndromic Deafness and the Associated Clinical Phenotypes: Experience from Two Tertiary Referral Centers

Abstract

Sensorineural hearing loss is one of the most common inherited sensory disorders. Functional classifications of deafness genes have shed light on genotype- and mechanism-based pharmacological approaches and on gene therapy strategies. In this study, we characterized the clinical phenotypes and genotypes of non-syndromic deafness caused by transcription factor (TF) gene variants, one of the functional classifications of genetic hearing loss. Of 1280 probands whose genomic DNA was subjected to molecular genetic testing, TF genes were responsible for hearing loss in 2.6%. Thirty-three pathogenic variants, including nine novel variants, accounting for non-syndromic deafness were clustered in only four TF genes (POU3F4, POU4F3, LMX1A, and EYA4), which is indicative of a narrow molecular etiologic spectrum of TF genes, and the functional redundancy of many other TF genes, in the context of non-syndromic deafness. The audiological and radiological characteristics associated with the four TF genes differed significantly, with a wide phenotypic spectrum. The results of this study reveal the genetic load of TF gene alterations among a cohort with non-syndromic hearing loss. Additionally, we have further refined the clinical profiles associated with TF gene variants as a basis for a personalized, genetically tailored approach to audiological rehabilitation.

Genetic Characteristics and Audiological Performance After Cochlear Implantation in Patients With Incomplete Partition Type III

“…In multivariable linear regression analysis that included age, sex, preoperative auditory threshold, other medical diseases, and genetic diagnosis, we could not find any significant factors to predict the outcomes (data not shown), which may be attributable to a small sample size of the patients. Although several patients (patients 3–6) underwent CI surgery at an older age and might have had confounding factors, such as a longer duration of hearing aid usage, these results were consistent with the previous literature, which contains long-term follow-up data revealing poorer performance of CI in patients with IP type III than in a control group with GJB2 mutations [ 18 , 19 ]. These data indicate that patients with IP type III may have a limited number of auditory neurons and a suboptimal structure for electrode insertion and stimulation, resulting in restricted long-term auditory performance.…”

WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome

“…Genomic DNA was extracted from peripheral blood using a standard procedure and subjected to initial screening with real-time PCR mutational hotspot screening kits targeting 22 variants of 10 hearing loss genes ( GJB2, SLC26A4, CDH23, TMPRSS3, MT-RNR1, OTOF, MPZL2, TMC1, COCH, and ATP1A3 ). [ 4 , 11 ] If these data were inconclusive, whole-exome sequencing was conducted to define the underlying molecular genetic etiology. Reads were aligned using the University of California Santa Cruz hg19 reference genome browser ( https://genome.ucsc.edu/ ) running Lasergene ver.…”

“…14 software (DNASTAR, Madison, WI, USA). As described previously,[ 4 – 10 ] stepwise filtering strategies were adopted to retrieve genetic variants. Candidate variants were validated employing Sanger sequencing, and segregation studies were performed using parental DNA samples.…”

“…More than 200 genes and > 150 different loci have been identified as contributors to hereditary hearing loss ( https://hereditaryhearingloss.org/ ) [ 3 ]. The genetic etiology aids our understanding of some types of genetic hearing loss in terms of clinical progress and application of optimized audiologic rehabilitation [ 4 – 12 ]. Moreover, functional classifications of genetic hearing loss, based on tonotopic expression patterns in the inner ear, as well as molecular insights from genetically engineered models, suggest promising approaches for targeted drug and gene therapy [ 13 ].…”

Molecular Genetic Etiology and Revisiting the Middle Ear Surgery Outcomes of Branchio-Oto-Renal Syndrome: Experience in a Tertiary Referral Center

“…14 software (DNASTAR, Madison, WI). As described previously (12)(13)(14)(15)(16)(17)(18), strict filtering was performed when retrieving genetic etiologies. Candidate variants were validated using Sanger sequencing, and segregation studies were performed using paternal DNA samples whenever possible.…”