Hearing Loss Phenotype Research Articles

Hearing loss phenotypes in Alport syndrome: experience in a tertiary referral center.

Despite previous reports of auditory phenotypes in Alport syndrome (AS), there have been no studies specifically addressing audiological phenotypes in South Korea. Herein, we elaborated on the audiological characteristics associated with AS based on their genotypes. We reviewed data from in-house AS patients between March 2014 and February 2023, excluding those without audiological documentation or genetic diagnoses. We retrieved medical history, hearing level, estimated glomerular filtration rate (eGFR), and genotypes from their medical records. The natural course of hearing loss and correlations between audiogram and eGFR were evaluated according to audio-gene profiles. Our study included 49 AS patients from 47 families, identifying 60 disease-causing variants, 45 of which were novel. All variants were classified as pathogenic or likely pathogenic based on ACMG-AMP guidelines. The auditory phenotypes of autosomal recessive AS (ARAS) and male X-linked AS (XLAS) patients demonstrated a progressive nature, with a down-sloping configuration. The ARAS with truncated variants exhibited an earlier onset of hearing loss than those with non-truncated variants. In male XLAS patients, the presence of truncated allele linked to more rapid hearing deterioration across all frequencies. In both ARAS and male XLAS patients, the presence of truncated allele was significantly associated with hearing severity and eGFR. Conversely, the majority of female XLAS and autosomal dominant AS maintained normal hearing levels without any correlation of eGFR, regardless of genotypes. This study detailed the auditory phenotypes and the auditory-renal association of AS at a tertiary center in South Korea, providing valuable references that guide auditory testing and rehabilitation strategies.

Polygenic Risk Scores and Hearing Loss Phenotypes in Children

Monogenic causes of childhood hearing loss are well established, as are polygenic risk contributions to age-related hearing loss. However, an untested possibility is that polygenic risk scores (PRS) also contribute to childhood hearing loss of all severities, alongside environmental and/or monogenic causes. To examine the association between a PRS for adult hearing loss and childhood hearing loss phenotypes. This cross-sectional study used a unique population-based dataset spanning normal hearing to profound loss, combining 2 contemporaneous population cohorts in Australia. This included the Child Health CheckPoint, a national population-based cross-sectional study nested within the Longitudinal Study of Australian Children, and the Victorian Childhood Hearing Longitudinal Databank (VicCHILD), a statewide population-based longitudinal data bank open to every child with congenital hearing loss in Victoria, Australia. The analysis took place from March to August 2023. Genotype data were generated from saliva- or blood-derived DNA using global single-nucleotide variations arrays. Based on genotype data, PRS was computed using published UK Biobank genome-wide association study results for self-reported hearing difficulty in individuals aged 40 to 69 years. Hearing outcomes were classified by laterality (bilateral, unilateral), severity (mild, moderate, severe or worse) and types (sensorineural, conductive, mixed, auditory neuropathy, atresia). Analyses included multinominal logistic regressions of PRS with hearing outcomes. Overall, 1488 CheckPoint study children (49.8% boys, aged 11-12 years) and 527 VicCHILD study children (55.2% boys, aged 0-13 years) with hearing and genotype data were included. A 1-SD increment in PRS was associated with higher odds of mild (odds ratio [OR], 1.3; 95% CI, 1.0-1.6), moderate (OR, 5.1; 95% CI, 3.2-8.1), and severe or worse (OR, 5.3; 95% CI, 3.9-7.3) unilateral hearing loss compared with normal hearing. Similarly, the PRS was associated with increased odds of mild, moderate, and severe or worse bilateral hearing loss (per-SD ORs, 3.9-6.6) and all hearing loss types (per-SD ORs, 8.5-10.6). In this cross-sectional study, a PRS initially developed for adult hearing difficulty was associated with wide-ranging childhood hearing loss phenotypes, partly explaining hearing phenotype variations despite shared genetic and environmental factors (eg, preterm birth). Large-scale studies with objectively defined hearing phenotypes are crucial for refining PRS and predicting high-risk children.

Study on the Correlation between SLC39A8 Gene and Body Constitution-related Phenotypes and Hearing loss: Based on a Mendelian Randomization analysis

IntroductionWe examined the role of hearing functions as potential mediators in relationships between noise exposures and abnormal body constitution-related results. Additionally, we employed Mendelian randomization (MR) to explore the causative connections between hearing problems and bodily composition.Material and methodsGene connections pertaining to phenotypes of hearing loss and body constitution were obtained from publically available summary data collected from adult population genome-wide association studies. Colocalization analysis was utilized to scrutinize the genetic associations pertaining to age-related hearing impairment (ARHI) liability and BMI within the SLC39A8 locus. For a comprehensive examination, we employed bi-directional MR encompassing both the 'forward' direction (from the composition of the body to hearing) and the 'reverse' direction.ResultsA common causative variable (rs13107325) for BMI and ARHI at the SLC39A8 locus was supported by colocalization analysis, which revealed that the two diseases shared the variant at the SLC39A8 gene. The forward analyses showed that body fat percentage (BFP) was significantly linked with the risk of ARHI [OR =0.95 (95% CI:0.93 to 0.98)] and that waist circumference (WC) was favorably associated with sensorineural hearing loss (SNHL) [OR=0.83 (95% CI:0.72 to 0.97)].ConclusionsWe couldn't find any proof to back up a causal relationship between constitution and HL in the reverse MR Analysis. Colocalization analysis recommended that SLC39A8 variant was often the source of high ARHI and BMI risk. In prospective MR, we discovered causal associations between WC and BFP with SNHL and ARHI, respectively. Therefore, our results suggest lipid metabolic abnormalities leading to adverse health outcome may lead to HL.

A Frameshift Variant in ANKRD24 Implicates Its Role in Human Non-Syndromic Hearing Loss.

Hearing loss (HL) is the most prevalent sensorineural disorders, affecting about one in 1000 newborns. Over half of the cases are attributed to genetic factors; however, due to the extensive clinical and genetic heterogeneity, many cases remain without a conclusive genetic diagnosis. The advent of next-generation sequencing methodologies in recent years has greatly helped unravel the genetic etiology of HL by identifying numerous genes and causative variants. Despite this, much remains to be uncovered about the genetic basis of sensorineural hearing loss (SNHL). Here, we report an Iranian consanguineous family with postlingual, moderate-to-severe autosomal recessive SNHL. After first excluding plausible variants in known deafness-causing genes using whole exome sequencing, we reanalyzed the data, using a gene/variant prioritization pipeline established for novel gene discovery for HL. This approach identified a novel homozygous frameshift variant c.1934_1937del; (p.Thr645Lysfs*52) in ANKRD24, which segregated with the HL phenotype in the family. Recently, ANKRD24 has been shown to be a pivotal constituent of the stereocilia rootlet in cochlea hair cells and interacts with TRIOBP, a protein already implicated in human deafness. Our data implicate for the first time, ANKRD24 in human nonsyndromic HL (NSHL) and expands the genetic spectrum of HL.

A base editor for the long-term restoration of auditory function in mice with recessive profound deafness.

A prevalent recessive mutation (c.2485C>T, p.Q829X) within the OTOF gene leads to profound prelingual hearing loss. Here we show that in Otof mice harbouring a mutation (c.2482C>T, p.Q828X) homozygous to human OTOF that faithfully mimics the hearing-loss phenotype, a base editor (consisting of the deaminase ABE7.10max and the Cas9 variant SpCas9-NG) packaged in adeno-associated viruses and injected into the inner ear of the mice via the round-window membrane effectively corrected the pathogenic mutation, with no apparent off-target effects. The treatment restored the levels of the otoferlin protein in 88% of the inner hair cells and stably rescued the auditory function of the mice to near-wild-type levels for over 1.5 years while improving synaptic exocytosis in the inner hair cells. We also show that an adenine base editor that targets the prevalent human OTOF mutation restored hearing in humanized mice to levels comparable to those of the wild-type counterparts. Base editors may be effective for the treatment of hereditary deafness.

A systematic review on the contribution of DNA methylation to hearing loss

BackgroundDNA methylation may have a regulatory role in monogenic sensorineural hearing loss and complex, polygenic phenotypic forms of hearing loss, including age-related hearing impairment or Meniere disease. The purpose of this systematic review is to critically assess the evidence supporting a functional role of DNA methylation in phenotypes associated with hearing loss.ResultsThe search strategy yielded a total of 661 articles. After quality assessment, 25 records were selected (12 human DNA methylation studies, 5 experimental animal studies and 8 studies reporting mutations in the DNMT1 gene). Although some methylation studies reported significant differences in CpG methylation in diverse gene promoters associated with complex hearing loss phenotypes (ARHI, otosclerosis, MD), only one study included a replication cohort that supported a regulatory role for CpG methylation in the genes TCF25 and POLE in ARHI. Conversely, several studies have independently confirmed pathogenic mutations within exon 21 of the DNMT1 gene, which encodes the DNA (cytosine-5)-methyltransferase 1 enzyme. This methylation enzyme is strongly associated with a rare disease defined by autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Of note, rare variants in DNMT1 and DNMT3A genes have also been reported in noise-induced hearing loss.ConclusionsEvidence supporting a functional role for DNA methylation in hearing loss is limited to few genes in complex disorders such as ARHI. Mutations in the DNMT1 gene are associated with ADCA-DN, suggesting the CpG methylation in hearing loss genes deserves further attention in hearing research.

A New Mouse Model for Usher Syndrome Crossing Kunming Mice with CBA/J Mice

BackgroundPreviously, we discovered a strain of Kunming mice, referred to as the KMush/ush strain, that exhibited notably abnormal electroretinogram (ERG) readings and elevated thresholds for auditory brainstem responses (ABRs), which resembled the characteristics of Usher Syndrome (USH). We successfully identified the pathogenic genes, Pde6b and Adgrv1, after KMush/ush crossbred with CBA/CaJ mice, referred to as CBA-1ush/ush, CBA-2ush/ush or CBA-2ush/ush. In this investigation, we crossbred KMush/ush and CBA/J mice to establish novel recombinant inbred lines and analysed their phenotypic and genotypic characteristics. MethodsERG readings, ABR testing, fundus morphology, histological examination of the retina and inner ear, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, western blotting, DNA sequence analysis and behavioural experiments were performed to assess the phenotypes and genotypes of the progeny lines. ResultsNo obvious waveforms in the ERG were detected in F1 hybrid mice while normal ABR results were recorded. The F2 hybrids, which were called J1ush/ush or J2ush/ush, exhibited segregated hearing-loss phenotypes. J1ush/ush mice had a retinitis pigmentosa (RP) phenotype with elevated ABR thresholds, whereas J2ush/ush mice exhibited only the RP phenotype. Interestingly, J1ush/ush mice showed significantly higher ABR thresholds than wild-type mice at 28 days post born (P28), and RT-qPCR and DNA-sequencing analysis showed that Adgrv1 gene expression was significantly altered in J1ush/ush mice, but histological analysis showed no significant structural changes in the organ of Corti or spiral ganglia. Further elevation of ABR-related hearing thresholds by P56 manifested only as a reduced density of spiral ganglion cells, which differed significantly from the previous pattern of cochlear alterations in CBA-2ush/ush mice. ConclusionsWe successfully introduced the hearing-loss phenotype of inbred mice with USH into CBA/J mice, which provides a good animal model for future studies on the important physiological roles of the Adgrv1 gene in inner-ear structure and for therapeutic studies targeting Adgrv1-mutated USH.

Reevaluating the splice-altering variant in TECTA as a cause of nonsyndromic hearing loss DFNA8/12 by functional analysis of RNA.

The aim of this study was to determine the genetic cause of early onset autosomal dominant hearing loss segregating in five-generation kindred of Chinese descent and provide preimplantation genetic testing (PGT)for them. Clinical examination, pedigree analysis and exome sequencing were carried out on the family. Minigene-based splicing analysis, in vivo RNA analysis and protein structure prediction by molecular modeling were conducted on the candidate variant. PGT for the causative variation and chromosome aneuploidis based on SNP analysis has been used for avoidance of hearing loss in this family. All the affected individuals presented with moderate down-sloping hearing loss and whole-exome sequencing identified a novel splice-site variant c.5383+6T>A in the tested subjects within the TECTA locus. Genotyping of all the 32 family members confirmed segregation of this variant and the hearing loss phenotype in the extended family. Functional analysis of RNA and molecular modeling indicates that c.5383+6T>A is a pathogenic splice-site variant and should be considered as genetic cause of the hearing loss. Furthermore, a successful singleton pregnancy with no variation in TECTA c.5383+6 was established and a healthy male child was born by PGT. We have identified a novel variant c.5383+6T>A in TECTA ZA-ZP inter-domain, which could be attributable to the early-onset autosomal dominant hearing loss. The implications of our study are valuable in elucidating the disrupted RNA splicing and uncovering the genetic cause of hearing loss with TECTA pathogenic variants, as well as providing reproductive approaches to healthy offspring.

A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study

Inherited hearing impairment is a remarkably heterogeneous monogenic condition, involving hundreds of genes, most of them with very small (< 1%) epidemiological contributions. The exception is GJB2, the gene encoding connexin-26 and underlying DFNB1, which is the most frequent type of autosomal recessive non-syndromic hearing impairment (ARNSHI) in most populations (up to 40% of ARNSHI cases). DFNB1 is caused by different types of pathogenic variants in GJB2, but also by large deletions that keep the gene intact but remove an upstream regulatory element that is essential for its expression. Such large deletions, found in most populations, behave as complete loss-of-function variants, usually associated with a profound hearing impairment. By using CRISPR-Cas9 genetic edition, we have generated a murine model (Dfnb1em274) that reproduces the most frequent of those deletions, del(GJB6-D13S1830). Dfnb1em274 homozygous mice are viable, bypassing the embryonic lethality of the Gjb2 knockout, and present a phenotype of profound hearing loss (> 90 dB SPL) that correlates with specific structural abnormalities in the cochlea. We show that Gjb2 expression is nearly abolished and its protein product, Cx26, is nearly absent all throughout the cochlea, unlike previous conditional knockouts in which Gjb2 ablation was not obtained in all cell types. The Dfnb1em274 model recapitulates the clinical presentation of patients harbouring the del(GJB6-D13S1830) variant and thus it is a valuable tool to study the pathological mechanisms of DFNB1 and to assay therapies for this most frequent type of human ARNSHI.

Associations of hearing loss and structural changes in specific cortical regions: a Mendelian randomization study.

Previous studies have suggested a correlation between hearing loss (HL) and cortical alterations, but the specific brain regions that may be affected are unknown. Genome-wide association study (GWAS) data for 3 subtypes of HL phenotypes, sensorineural hearing loss (SNHL), conductive hearing loss, and mixed hearing loss, were selected as exposures, and GWAS data for brain structure-related traits were selected as outcomes. The inverse variance weighted method was used as the main estimation method. Negative associations were identified between genetically predicted SNHL and brain morphometric indicators (cortical surface area, cortical thickness, or volume of subcortical structures) in specific brain regions, including the bankssts (β = -0.006mm, P = 0.016), entorhinal cortex (β = -4.856mm2, P = 0.029), and hippocampus (β = -24.819cm3, P = 0.045), as well as in brain regions functionally associated with visual perception, including the pericalcarine (β = -10.009cm3, P = 0.013). Adaptive changes and functional remodeling of brain structures occur in patients with genetically predicted HL. Brain regions functionally associated with auditory perception, visual perception, and memory function are the main brain regions vulnerable in HL.

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

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.

Soft classification and regression analysis of audiometric phenotypes of age-related hearing loss.

Age-related hearing loss has a complex etiology. Researchers have made efforts to classify relevant audiometric phenotypes, aiming to enhance medical interventions and improve hearing health. We leveraged existing pattern analyses of age-related hearing loss and implemented the phenotype classification via quadratic discriminant analysis (QDA). We herein propose a method for analyzing the exposure effects on the soft classification probabilities of the phenotypes via estimating equations. Under reasonable assumptions, the estimating equationsare unbiased and lead to consistent estimators. The resulting estimator had good finite sample performances in simulation studies. As an illustrative example, we applied our proposed methods to assess the association between a dietary intake pattern, assessed as adherence scores for the dietary approaches to stop hypertension diet calculated using validated food-frequency questionnaires, and audiometric phenotypes (older-normal, metabolic, sensory, and metabolic plus sensory), determined based on data obtained in the Nurses' Health Study II Conservation of Hearing Study, the Audiology Assessment Arm. Our findings suggested that participants with a more healthful dietary pattern were less likely to develop the metabolic plus sensory phenotype of age-related hearing loss.

Genetic and phenotypic analysis of MYO15A rare variants associated with autosomal recessive hearing loss

Objective:To analyze the phenotype and genotype characteristics of autosomal recessive hearing loss caused by MYO15A gene variants, and to provide genetic diagnosis and genetic counseling for patients and their families. Methods:Identification of MYO15A gene variants by next generation sequencing in two sporadic cases of hearing loss at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The sequence variants were verified by Sanger sequencing.The pathogenicity of these variants was determined according to the American College of Medical Genetics and Genomics（ACMG） variant classification guidelines, in conjuction with clinical data. Results:The probands of the two families have bilateral,severe or complete hearing loss.Four variants of MYO15A were identified, including one pathogenic variant that has been reported, two likely pathogenic variants,and one splicing variant of uncertain significance. Patient I carries c. 3524dupA（p. Ser1176Valfs*14）, a reported pathogenic variant, and a splicing variant c. 10082+3G>A of uncertain significance according to the ACMG guidelines. Patient I was treated with bilateral hearing aids with satisfactory effect, demonstrated average hearing thresholds of 37.5 dB in the right ear and 33.75 dB in the left ear. Patient Ⅱ carries c. 7441_7442del（p. Leu2481Glufs*86） and c. 10250_10252del（p. Ser3417del）,a pair of as likely pathogenic variants according to the ACMG guidelines. Patient Ⅱ, who underwent right cochlear implantation eight years ago, achieved scores of 9 on the Categorical Auditory Performance-Ⅱ（CAP-Ⅱ） and 5 on the Speech Intelligibility Rating（SIR）. Conclusion:This study's discovery of the rare c. 7441_7442del variant and the splicing variant c. 10082+3G>A in the MYO15A gene is closely associated with autosomal recessive hearing loss, expanding the MYO15A variant spectrum. Additionally, the pathogenicity assessment of the splicing variant facilitates classification of splicing variations.

Novel, pathogenic insertion variant of GSDME associates with autosomal dominant hearing loss in a large Chinese pedigree.

Nonsyndromic hearing loss (NSHL) is a genetically diverse, highly heterogeneous condition characterised by deafness, and Gasdermin E (GSDME) variants have been identified as directly inducing autosomal dominant NSHL. While many NSHL cases associated with GSDME involve the skipping of exon 8, there is another, less understood pathogenic insertion variant specifically found in Chinese pedigrees that causes deafness, known as autosomal dominant 5 (DFNA5) hearing loss. In this study, we recruited a large Chinese pedigree, conducted whole-exome and Sanger sequencing to serve as a comprehensive clinical examination, and extracted genomic DNA samples for co-segregation analysis of the members. Conservation and expression analyses for GSDME were also conducted. Our clinical examinations revealed an autosomal dominant phenotype of hearing loss in the family. Genetic analysis identified a novel insertion variant in GSDME exon 8 (GSDME: NM_004403.3: c.1113_1114insGGGGTGCAGCTTACAGGGTGGGTGT: p. P372fs*36). This variant is segregated with the deafness phenotype of this pedigree. The GSDME gene was highly conserved in the different species we analysed, and its mRNA expression was ubiquitously low in different human tissues. In conclusion, we have successfully identified a novel pathogenic insertion variant of GSDME in a Chinese pedigree that causes deafness, shedding light on the genetic basis of hearing loss within this specific family. Our findings expand the spectrum of known variants associated with GSDME-related deafness and may further support both the underlying gain-of-function mechanism and functional associations of GSDME hearing loss variants.

Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia.

Anophthalmia and microphthalmia are severe developmental ocular disorders that affect the size of the ocular globe and can be unilateral or bilateral. The disease is found in syndromic as well as non-syndromic forms. It is genetically caused by chromosomal aberrations, copy number variations and single gene mutations, along with non-genetic factors such as viral infections, deficiency of vitamin A and an exposure to alcohol or drugs during pregnancy. To date, more than 30 genes having different modes of inheritance patterns are identified as causing anophthalmia and microphthalmia. In the present study, a clinical and genetic analysis was performed of six patients with anophthalmia and microphthalmia and/or additional phenotypes of intellectual disability, developmental delay and cerebral palsy from a large consanguineous Pakistani family. Whole exome sequencing followed by data analysis for variants prioritization and validation through Sanger sequencing was performed to identify the disease causing variant(s). American College of Medical Genetics and Genomics (ACMG) guidelines were applied to classify clinical interpretation of the prioritized variants. Clinical investigations revealed that the affected individuals are afflicted with anophthalmia. Three of the patients showed additional phenotype of intellectual disability, developmental delays and other neurological symptoms. Whole exome sequencing of the DNA samples of the affected members in the family identified a novel homozygous stop gain mutation (NM_012186: c.106G>T: p.Glu36*) in Forkhead Box E3 (FOXE3) gene shared by all affected individuals. Moreover, patients segregating additional phenotypes of spastic paraplegia, intellectual disability, hearing loss and microcephaly showed an additional homozygous sequence variant (NM_004722: c.953G>A: p.Arg318Gln) in AP4M1. Sanger sequencing validated the correct segregation of the identified variants in the affected family. ACMG guidelines predicted the variants to be pathogenic. We have investigated first case of syndromic anophthalmia caused by variants in the FOXE3 and AP4M1. The present findings are helpful for understanding pathological role of the mutations of the genes in syndromic forms of anophthalmia. Furthermore, the study signifies searching for the identification of second variant in families with patients exhibiting variable phenotypes. In addition, the findings will help clinical geneticists, genetic counselors and the affected family with respect to prenatal testing, family planning and genetic counseling.

The natural history, clinical outcomes, and genotype-phenotype relationship of otoferlin-related hearing loss: a systematic, quantitative literature review.

Congenital hearing loss affects one in 500 newborns. Sequence variations in OTOF, which encodes the calcium-binding protein otoferlin, are responsible for 1-8% of congenital, nonsyndromic hearing loss and are the leading cause of auditory neuropathy spectrum disorders. The natural history of otoferlin-related hearing loss, the relationship between OTOF genotype and hearing loss phenotype, and the outcomes of clinical practices in patients with this genetic disorder are incompletely understood because most analyses have reported on small numbers of cases with homogeneous OTOF genotypes. Here, we present the first systematic, quantitative literature review of otoferlin-related hearing loss, which analyzes patient-specific data from 422 individuals across 61 publications. While most patients display a typical phenotype of severe-to-profound hearing loss with prelingual onset, 10-15% of patients display atypical phenotypes, including mild-to-moderate, progressive, and temperature-sensitive hearing loss. Patients' phenotypic presentations appear to depend on their specific genotypes. For example, non-truncating variants located in and immediately downstream of the C2E calcium-binding domain are more likely to produce atypical phenotypes. Additionally, the prevalence of certain sequence variants and their associated phenotypes varies between populations due to evolutionary founder effects. Our analyses also suggest otoacoustic emissions are less common in older patients and those with two truncating OTOF variants. Critically, our review has implications for the application and limitations of clinical practices, including newborn hearing screenings, hearing aid trials, cochlear implants, and upcoming gene therapy clinical trials. We conclude by discussing the limitations of available research and recommendations for future studies on this genetic cause of hearing loss.

Impacts of an age-related hearing loss allele of cadherin 23 on severity of hearing loss in ICR and NOD/Shi mice

The age-related hearing loss allele (Cdh23ahl) of the cadherin 23 gene leads to a more severe hearing loss phenotype through additive effects with risk alleles for hearing loss. In this study, we genome edited the Cdh23ahl allele to the wild-type Cdh23+ allele in outbred ICR mice and inbred NOD/Shi mice established from ICR mice and investigated their effects on hearing phenotypes. Several hearing tests confirmed that ICR mice developed early onset high-frequency hearing loss and exhibited individual differences in hearing loss onset times. Severe loss of cochlear hair cells was also detected in the high-frequency areas in ICR mice. These phenotypes were rescued by genome editing the Cdh23ahl allele to Cdh23+, suggesting that abnormal hearing phenotypes develop because of the interaction of the Cdh23ahl and risk alleles in the genetic background of ICR mice. NOD/Shi mice developed more severe hearing loss and hair cell degeneration than ICR mice. Hearing loss was detected at 1 month old. Hair cell loss, including degeneration of cell bodies and stereocilia, was observed in all regions of the cochlea in NOD/Shi mice. Although these phenotypes were partially rescued by genome editing to the Cdh23+ allele, the phenotypes associated with high-frequency hearing were mostly unrecovered in NOD/Shi mice. These results strongly suggest that the genetic background of NOD/Shi mice contain a potential risk allele for the acceleration of early onset high-frequency hearing loss.

Can MRI biomarkers for hearing loss in enlarged vestibular aqueduct be measured reproducibly?

Morphological features of an enlarged endolymphatic duct (ED) and sac (ES) are imaging biomarkers for genotype and hearing loss phenotype. We determine which biomarkers can be measured in a reproducible manner, facilitating further clinical prediction studies in enlarged vestibular aqueduct hearing loss. A rater reproducibility study. Three consultant radiologists independently measured previously reported MRI ED & ES biomarkers (ED midpoint width, maximal ED diameter closest to the vestibule, ES length, ES width and presence of ES signal heterogeneity) and presence of incomplete partition Type 2 from 80 ears (T2 weighted axial MRI). Interclass correlation coefficients (ICC) and Gwet's Agreement Coefficients (AC) were generated to give a measure of reproducibility for both continuous and categorical feature measures respectively. ES length, width and sac signal heterogeneity showed adequate reproducibility (ICC 95% confidence intervals 0.77-0.95, Gwet's AC for sac heterogeneity 0.64). When determining ED midpoint width, measurements from multiple raters are required for "good" reliability (ICC 95% CI 0.75-0.89). Agreement on the presence of incomplete partition Type 2 ranged from "moderate" to "substantial". Regarding MR imaging, the opinion of multiple expert raters should be sought when determining the presence of an enlarged ED defined by midpoint width. ED midpoint, ES length, width and signal heterogeneity have adequate reproducibility to be further explored as clinical predictors for audiological phenotype. We report which ED & ES biomarkers are reproducibly measured. Researchers can confidently utilise these specific biomarkers when modelling progressive hearing loss associated with enlarged vestibular aqueduct.

Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations

Objective: To analyze the phenotypic-genotypic characteristics of hereditary deafness caused by OTOA gene variations. Methods: Family histories, clinical phenotypes and gene variations of six pedigrees were analyzed, which were diagnosed with hearing loss caused by OTOA gene variations at the PLA General Hospital from September 2015 to January 2022. The sequence variations were verified by Sanger sequencing and the copy number variations were validated by multiplex ligation-dependent probe amplification (MLPA) in the family members. Results: The hearing loss phenotype caused by OTOA variations ranged from mild to moderate in the low frequencies, and from moderate to severe in the high frequencies in the probands, which came from six sporadic pedigrees, among which a proband was diagnosed as congenital deafness and five were diagnosed as postlingual deafness. One proband carried homozygous variations and five probands carried compound heterozygous variations in OTOA gene. Nine pathogenic variations (six copy number variations, two deletion variations and one missense variation) and two variations with uncertain significance in OTOA were identified in total, including six copy number variations and five single nucleotide variants, and three of the five single nucleotide variants were firstly reported [c.1265G>T(p.Gly422Val),c.1534delG(p.Ala513Leufs*11) and c.3292C>T(p.Gln1098fs*)]. Conclusions: OTOA gene variations can lead to autosomal recessive nonsyndromic hearing loss. In this study, the hearing loss caused by OTOA defects mostly presents as bilateral, symmetrical, and postlingual, and that of a few presents as congenital. The pathogenic variations of OTOA gene are mainly copy number variations followed by deletion variations and missense variations.

Overlooked KCNQ4 variants augment the risk of hearing loss

Pathogenic variants of KCNQ4 cause symmetrical, late-onset, progressive, high-frequency-affected hearing loss, which eventually involves all frequencies with age. To understand the contribution of KCNQ4 variants to hearing loss, we analyzed whole-exome and genome sequencing data from patients with hearing loss and individuals whose hearing phenotypes were unknown. In KCNQ4, we identified seven missense variants and one deletion variant in 9 hearing loss patients and 14 missense variants in the Korean population with an unknown hearing loss phenotype. The p.R420W and p.R447W variants were found in both cohorts. To investigate the effects of these variants on KCNQ4 function, we performed whole-cell patch clamping and examined their expression levels. Except for p.G435Afs*61, all KCNQ4 variants exhibited normal expression patterns similar to those of wild-type KCNQ4. The p.R331Q, p.R331W, p.G435Afs*61, and p.S691G variants, which were identified in patients with hearing loss, showed a potassium (K+) current density lower than or similar to that of p.L47P, a previously reported pathogenic variant. The p.S185W and p.R216H variants shifted the activation voltage to hyperpolarized voltages. The channel activity of the p.S185W, p.R216H, p.V672M, and p.S691G KCNQ4 proteins was rescued by the KCNQ activators retigabine or zinc pyrithione, whereas p.G435Afs*61 KCNQ4 proteins were partially rescued by sodium butyrate, a chemical chaperone. Additionally, the structure of the variants predicted using AlphaFold2 showed impaired pore configurations, as did the patch-clamp data. Our findings suggest that KCNQ4 variants may be overlooked in hearing loss that starts in adulthood. Some of these variants are medically treatable; hence, genetic screening for KCNQ4 is important.