RESUMO
OBJECTIVES: Recessive variants in the MYO15A gene constitute an important cause of sensorineural hearing impairment (SNHI). However, the clinical features of MYO15A-related SNHI have not been systemically investigated. This study aimed to delineate the hearing features and outcomes in patients with pathogenic MYO15A variants. DESIGN: This study recruited 40 patients with biallelic MYO15A variants from 31 unrelated families. The patients were grouped based on the presence of N-terminal domain variants (N variants). The longitudinal audiological data and for those undergoing cochlear implantation, the auditory and speech performance with cochlear implants, were ascertained and compared between patients with different genotypes. RESULTS: At the first audiometric examination, 32 patients (80.0%) presented with severe to profound SNHI. Patients with at least one allele of the N variant exhibited significantly better hearing levels than those with biallelic non-N variants (78.2 ± 23.9 dBHL and 94.7 ± 22.8 dBHL, respectively) (p = 0.033). Progressive SNHI was observed in 82.4% of patients with non-profound SNHI, in whom the average progression rate of hearing loss was 6.3 ± 4.8 dBHL/year irrespective of the genotypes. Most of the 25 patients who underwent cochlear implantation exhibited favorable auditory and speech performances post-implantation. CONCLUSIONS: The hearing features of patients with biallelic pathogenic MYO15A variants are characterized by severe to profound SNHI, rapid hearing progression, and favorable outcomes with cochlear implants. Periodic auditory monitoring is warranted for these patients to enable early intervention.
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Implante Coclear , Implantes Cocleares , Surdez , Perda Auditiva Neurossensorial , Percepção da Fala , Surdez/cirurgia , Audição , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/cirurgia , Testes Auditivos , Humanos , Miosinas/genética , Resultado do TratamentoRESUMO
Recessive variants of the SLC26A4 gene are globally a common cause of hearing impairment. In the past, cell lines and transgenic mice were widely used to investigate the pathogenicity associated with SLC26A4 variants. However, discrepancies in pathogenicity between humans and cell lines or transgenic mice were documented for some SLC26A4 variants. For instance, the p.C565Y variant, which was reported to be pathogenic in humans, did not exhibit functional pathogenic consequences in cell lines. To address the pathogenicity of p.C565Y, we used a genotype-based approach in which we generated knock-in mice that were heterozygous (Slc26a4+/C565Y), homozygous (Slc26a4C565Y/C565Y), and compound heterozygous (Slc26a4919-2A>G/C565Y) for this variant. Subsequent phenotypic characterization revealed that mice with these genotypes demonstrated normal auditory and vestibular functions, and normal inner-ear morphology and pendrin expression. These findings indicate that the p.C565Y variant is nonpathogenic for mice, and that a single p.C565Y allele is sufficient to maintain normal inner-ear physiology in mice. Our results highlight the differences in pathogenicity associated with certain SLC26A4 variants between transgenic mice and humans, which should be considered when interpreting the results of animal studies for SLC26A4-related deafness.
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Modelos Animais de Doenças , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Perda Auditiva Neurossensorial/genética , Mutação , Transportadores de Sulfato/genética , Animais , Genótipo , Perda Auditiva Neurossensorial/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fenótipo , Transportadores de Sulfato/fisiologia , Aqueduto Vestibular/metabolismo , Aqueduto Vestibular/patologiaRESUMO
Hearing loss is the most prevalent hereditary sensory disorder in children. Approximately 2 in 1000 infants are affected by genetic hearing loss. The PJVK gene, which encodes the pejvakin protein, has been linked to autosomal recessive non-syndromic hearing loss DFNB59. Previous clinical studies have revealed that PJVK mutations might be associated with a wide spectrum of auditory manifestations, ranging from hearing loss of pure cochlear origin to that involving the retrocochlear central auditory pathway. The phenotypic variety makes the pathogenesis of this disease difficult to determine. Similarly, mouse models carrying different Pjvk defects show phenotypic variability and inconsistency. In this study, we generated a knockin mouse model carrying the c.874G > A (p.G292R) variant to model and investigate the auditory and vestibular phenotypes of DFNB59.
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Modelos Animais de Doenças , Perda Auditiva Neurossensorial/genética , Proteínas/genética , Animais , Sistemas CRISPR-Cas , Técnicas de Introdução de Genes , Células Ciliadas Auditivas/patologia , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação de Sentido Incorreto , Gânglio Espiral da Cóclea/patologia , Vestíbulo do Labirinto/fisiopatologiaRESUMO
OBJECTIVES: Recessive mutations in GJB2 are the most common genetic cause of sensorineural hearing impairment (SNHI) in humans. SNHI related to GJB2 mutations demonstrates a wide variation in audiological features, and there has been no reliable prediction model for hearing outcomes until now. The objectives of this study were to clarify the predominant factors determining hearing outcome and to establish a predictive model for SNHI in patients with GJB2 mutations. DESIGN: A total of 434 patients confirmed to have biallelic GJB2 mutations were enrolled and divided into three groups according to their GJB2 genotypes. Audiological data, including hearing levels and audiogram configurations, were compared between patients with different genotypes. Univariate and multivariate generalized estimating equation (GEE) analyses were performed to analyze longitudinal data of patients with multiple audiological records. RESULTS: Of the 434 patients, 346 (79.7%) were homozygous for the GJB2 p.V37I mutation, 55 (12.7%) were compound heterozygous for p.V37I and another GJB2 mutation, and 33 (7.6%) had biallelic GJB2 mutations other than p.V37I. There was a significant difference in hearing level and the distribution of audiogram configurations between the three groups. Multivariate GEE analyses on 707 audiological records of 227 patients revealed that the baseline hearing level and the duration of follow-up were the predominant predictors of hearing outcome, and that hearing levels in patients with GJB2 mutations could be estimated based on these two parameters: (Predicted Hearing Level [dBHL]) = 3.78 + 0.96 × (Baseline Hearing Level [dBHL]) + 0.55 × (Duration of Follow-Up [y]). CONCLUSION: The baseline hearing level and the duration of follow-up are the main prognostic factors for outcome of GJB2-related SNHI. These findings may have important clinical implications in guiding follow-up protocols and designing treatment plans in patients with GJB2 mutations.
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Conexina 26 , Conexinas , Perda Auditiva Neurossensorial , Conexina 26/genética , Conexinas/genética , Genótipo , Perda Auditiva Neurossensorial/genética , Humanos , MutaçãoRESUMO
BACKGROUND: Eustachian tube dysfunction (ETD) is a common otolaryngological disorder. The seven-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) was used for the assessment of symptoms related to ETD and treatment outcome. Currently, there is no traditional Chinese version of the ETDQ-7 to diagnose ETD in Taiwan. We aim to verify the reliability and validity of the traditional Chinese version of the ETDQ-7 in a clinical setting. METHODS: The traditional Chinese version of the ETDQ-7 was completed by 60 adult subjects composed of 30 healthy controls and 30 subjects diagnosed with ETD. The internal consistency was evaluated using the Cronbach's α coefficient. The discriminant validity was calculated by receiver operating characteristic (ROC) curve as an accuracy measure. RESULTS: The overall Cronbach's α coefficient of the traditional Chinese version ETDQ-7 was 0.717. The mean ETDQ-7 total score was 26.97 in the ETD group and 9.27 in the control group. The area under the ROC curve (AUC) was 99.8%, and the sensitivity and specificity of the traditional Chinese ETDQ-7 was 100% and 99.9%, respectively. CONCLUSION: The traditional Chinese version of the ETDQ-7 is a valid and reliable, disease-specific rating scale that can be used to quantitatively evaluate the severity of subjective symptoms of ETD in adult patients.
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Otopatias/diagnóstico , Tuba Auditiva/fisiopatologia , Inquéritos e Questionários , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Taiwan , Traduções , Adulto JovemRESUMO
Excessive levels of reactive oxygen species (ROS) lead to mitochondrial damage and apoptotic cell death in gentamicin-induced ototoxicity. 2,3,4',5-Tetrahydroxystilbene-2-O-ß-d-glucoside (THSG), a bioactive constituent, isolated from Polygonum multiflorum Thunb., exhibits numerous biological benefits in treating aging-related diseases by suppressing oxidative damage. However, its protective effect on gentamicin-induced ototoxicity remains unexplored. Therefore, here, we aimed to investigate the otoprotective effect of THSG on gentamicin-induced apoptosis in mouse cochlear UB/OC-2 cells. We evaluated the effect of gentamicin and THSG on the ROS level, superoxide dismutase (SOD) activity, mitochondrial membrane potential, nuclear condensation, and lactate dehydrogenase (LDH) release, and the expression of apoptosis-related proteins was assessed to understand the molecular mechanisms underlying its preventive effects. The findings demonstrated that gentamicin increased ROS generation, LDH release, and promoted apoptotic cell death in UB/OC-2 cells. However, THSG treatment reversed these effects by suppressing ROS production and downregulating the mitochondrial-dependent apoptotic pathway. Additionally, it increased the SOD activity, decreased the expression of apoptosis-related proteins, alleviated the levels of the apoptotic cells, and impaired cytotoxicity. To the best of our knowledge, this is the first study to demonstrate that THSG could be a potential therapeutic option to attenuate gentamicin-induced ototoxicity.
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Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Gentamicinas/efeitos adversos , Glucosídeos/farmacologia , Mitocôndrias/efeitos dos fármacos , Ototoxicidade/prevenção & controle , Estilbenos/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fallopia multiflora/química , Fallopia multiflora/metabolismo , Gentamicinas/farmacologia , Gentamicinas/toxicidade , L-Lactato Desidrogenase/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Ototoxicidade/complicações , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVES: The purpose of the study is to investigate feasibility of early activation after cochlear implantation by evaluating long-term impedance change and speech perception. DESIGN: Case-control study SETTING: Between July 2015 and December 2016, we prospectively enrolled 20 subjects for early activation (within 24 hours after cochlear implantation). On the other hand, from November 2013 to July 2015, 20 age- and sex-matched control subjects from the database of cochlear implantees treated with conventional activation schedule (4 weeks after surgery) were retrospectively enrolled. PARTICIPANT: Forty patients who underwent cochlear implantation surgeries. MAIN OUTCOME MEASURES: The series impedance and speech perception score of both groups were compared. RESULTS: No statistical difference in long-term follow-up between the two groups was found using GEEs and multivariate analysis. In the early activation group, impedance reached a steady level by the 2nd postoperative week, and the hearing perception ability significantly improved by the 4th postoperative week. CONCLUSION: This comparative study illustrated sequential impedance data during early activation (24 hours) and conventional activation (4 weeks) after CI surgery. There were no major complications in either group, and the safety of early activation with respect to impedance changes, postoperative residual hearing preservation and speech perception scores were non-inferior to that of the conventional group. Therefore, in this study, we established the feasibility of early activation 24 hours after cochlear implantation.
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Implante Coclear , Implantes Cocleares , Transtornos da Audição/terapia , Percepção da Fala/fisiologia , Testes de Impedância Acústica , Adolescente , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Transtornos da Audição/fisiopatologia , Transtornos da Audição/psicologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To evaluate the feasibility and potential benefits of incorporating genetic and cytomegalovirus (CMV) screenings into the current newborn hearing screening (NHS) programs. STUDY DESIGN: Newborns were recruited prospectively from a tertiary hospital and a maternity clinic between May 2016 and December 2016 and were subjected to hearing screening, CMV screening, and genetic screening for 4 common mutations in deafness genes (p.V37I and c.235delC of GJB2 gene, c.919-2A>G of SLC26A4 gene, and the mitochondrial m.1555A>G). Infants with homozygous nuclear mutations or homoplasmic/heteroplasmic mitochondrial mutation (referred to as "conclusively positive genotypes") and those who tested positive for CMV received diagnostic audiologic evaluations. RESULTS: Of the total 1716 newborns enrolled, we identified 20 (1.2%) newborns with conclusively positive genotypes on genetic screening, comprising 15 newborns (0.9%) with GJB2 p.V37I/p.V37I and 5 newborns (0.3%) with m.1555A>G. Three (0.2%) newborns tested positive on CMV screening. Twelve of the 20 newborns (60%) with conclusively positive genotypes and all 3 newborns who tested positive for CMV (100%) passed NHS at birth. Diagnostic audiologic evaluations conducted at 3 months confirmed hearing impairment in 6 of the 20 infants (30%) with conclusively positive genotypes. CONCLUSIONS: This study confirms the feasibility of performing hearing, genetic, and CMV screenings concurrently in newborns and provides evidence that the incorporation of these screening tests could potentially identify an additional subgroup of infants with impaired hearing that might not be detected by the NHS programs.
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Audiometria , Infecções por Citomegalovirus/diagnóstico , Surdez/diagnóstico , Testes Genéticos/métodos , Triagem Neonatal/métodos , Surdez/genética , Estudos de Viabilidade , Feminino , Seguimentos , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Recém-Nascido , Masculino , Mutação , Estudos Prospectivos , TaiwanRESUMO
PURPOSE: The feasibility of genetic screening for deafness-causing mutations in newborns has been reported in several studies. The aim of this study was to investigate the long-term results in those who screened positive for deafness mutations; these results are crucial to determine the cost-effectiveness to justify population-wide genetic screening. METHODS: We performed simultaneous hearing screening and genetic screening targeting four common deafness mutations (p.V37I and c.235delC of GJB2, c.919-2A>G of SLC26A4, and the mitochondrial m.1555A>G) in 5173 newborns at a tertiary hospital between 2009 and 2015. Serial audiometric results up to 6 years old were then analyzed in children with conclusive genotypes. RESULTS: Newborn genetic screening identified 82 (1.6%) babies with conclusive genotypes, comprising 62 (1.2%) with GJB2 p.V37I/p.V37I, 16 (0.3%) with GJB2 p.V37I/c.235delC, and 4 (0.1%) with m.1555A>G. Of these, 46 (56.1%) passed hearing screening at birth. Long-term follow-up demonstrated progressive hearing loss in children with the GJB2 p.V37I/p.V37I and p.V37I/c.235delC genotypes; this hearing loss deteriorated by approximately 1 decibel hearing level (dBHL) per year. CONCLUSIONS: We delineated the longitudinal auditory features of the highly prevalent GJB2 p.V37I mutation on a general population basis and confirmed the utility of newborn genetic screening in identifying infants with late-onset or progressive hearing impairment undetectable by newborn hearing screening.Genet Med 19 1, 6-12.
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Conexinas/genética , Perda Auditiva/genética , Proteínas de Membrana Transportadoras/genética , Triagem Neonatal , Audiometria , Criança , Pré-Escolar , Conexina 26 , DNA Mitocondrial/genética , Feminino , Genótipo , Perda Auditiva/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Transportadores de SulfatoAssuntos
Implante Coclear/métodos , Síndrome LEOPARD/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Gradenigo syndrome is a rare but devastating complication of otitis media that involves the petrous apex. Clinically, it is characterized by the triad of suppurative otitis media, deep facial pain, and abducens palsy. Most of the Gradenigo syndrome cases that have been reported in the literature were caused by pyogenic bacteria. In this report, we describe the clinical courses of 4 adults with Gradenigo syndrome who were encountered consecutively at a tertiary referral hospital between 2008 and 2012. Mycobacterium abscessus was confirmed in all 4 cases by culturing the pathological tissues obtained during surgical debridement. To the best of our knowledge, this is the first report documenting infections of nontuberculous mycobacteria (NTM) in Gradenigo syndrome. An NTM infection must be considered in chronic otomastoiditis complicated by Gradenigo syndrome. The definite treatment of Gradenigo syndrome with an NTM infection requires adequate surgical debridement combined with antibiotic treatment for at least 4-6 months.
Assuntos
Infecções por Mycobacterium não Tuberculosas , Micobactérias não Tuberculosas/isolamento & purificação , Petrosite/microbiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Aminoglycoside- and cisplatin-induced ototoxicity, which is a significant issue owing to the widespread use of these drugs in clinical practice, involves the entry of aminoglycosides and cisplatin into the endolymph and hair cells via specific channels or transporters, followed by reactive oxygen species (ROS) generation and hair cells apoptosis. Current strategies focalize primarily on interference with downstream ROS effects; however, recent evidence has demonstrated that inhibiting the uptake of aminoglycosides and cisplatin by hair cells is another promising strategy for tackling the upstream drug uptake pathway. With advances in structural biology, the conformations of certain aminoglycoside and cisplatin channels and transporters, such as the mechanoelectrical transduction channel and organic cation transporter-2, have been largely elucidated. These channels and transporters may become potential targets for the introduction of new otoprotective strategies. This review focuses on the strategies for inhibiting ototoxic drugs uptake by auditory hair cells and provides potential targets for recent developments in the field of otoprotection. Molecular dynamics (MD) simulations of these proteins could help identify the molecules that inhibit the uptake of aminoglycosides and cisplatin by hair cells. Integrating upstream drug uptake pathway targets and MD simulations may help dissect molecular mechanisms and develop novel otoprotective strategies for aminoglycoside- and cisplatin-induced ototoxicity.
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Antineoplásicos , Ototoxicidade , Humanos , Cisplatino/toxicidade , Aminoglicosídeos/efeitos adversos , Antineoplásicos/toxicidade , Ototoxicidade/prevenção & controle , Espécies Reativas de Oxigênio , Antibacterianos/farmacologia , ApoptoseRESUMO
BACKGROUND: Recessive GJB2 variants, the most common genetic cause of hearing loss, may contribute to progressive sensorineural hearing loss (SNHL). The aim of this study is to build a realistic predictive model for GJB2-related SNHL using machine learning to enable personalized medical planning for timely intervention. METHOD: Patients with SNHL with confirmed biallelic GJB2 variants in a nationwide cohort between 2005 and 2022 were included. Different data preprocessing protocols and computational algorithms were combined to construct a prediction model. We randomly divided the dataset into training, validation, and test sets at a ratio of 72:8:20, and repeated this process ten times to obtain an average result. The performance of the models was evaluated using the mean absolute error (MAE), which refers to the discrepancy between the predicted and actual hearing thresholds. RESULTS: We enrolled 449 patients with 2184 audiograms available for deep learning analysis. SNHL progression was identified in all models and was independent of age, sex, and genotype. The average hearing progression rate was 0.61 dB HL per year. The best MAE for linear regression, multilayer perceptron, long short-term memory, and attention model were 4.42, 4.38, 4.34, and 4.76 dB HL, respectively. The long short-term memory model performed best with an average MAE of 4.34 dB HL and acceptable accuracy for up to 4 years. CONCLUSIONS: We have developed a prognostic model that uses machine learning to approximate realistic hearing progression in GJB2-related SNHL, allowing for the design of individualized medical plans, such as recommending the optimal follow-up interval for this population.
Assuntos
Conexina 26 , Perda Auditiva Neurossensorial , Aprendizado de Máquina , Humanos , Conexina 26/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Feminino , Masculino , Adulto , Criança , Adolescente , Pessoa de Meia-Idade , Pré-EscolarRESUMO
Pathogenic variants of the WFS1 gene can cause recessive-inherited Wolfram syndrome or dominant-inherited Wolfram-like syndrome with optic atrophy and hearing impairment. Using the Sendai virus delivery system, we generated induced pluripotent stem cells from the peripheral blood mononuclear cells of a female patient with the WFS1 pathogenic variant c.2051C > T (p.Ala684Val). The resulting induced pluripotent stem cells exhibited a normal karyotype and pluripotency, as confirmed using immunofluorescence staining, and differentiated into three germ layers in vivo. This cellular model provides a useful platform for investigating the pathogenic mechanisms of both blindness and deafness related to WFS1 variants.
Assuntos
Perda Auditiva , Células-Tronco Pluripotentes Induzidas , Síndrome de Wolfram , Humanos , Feminino , Células-Tronco Pluripotentes Induzidas/patologia , Leucócitos Mononucleares/patologia , Perda Auditiva/genética , Síndrome de Wolfram/genética , Síndrome de Wolfram/patologia , MutaçãoRESUMO
Variants in the gap junction beta-2 (GJB2) gene are the most common cause of hereditary hearing impairment. However, how GJB2 variants lead to local physicochemical and structural changes in the hexameric ion channels of connexin 26 (Cx26), resulting in hearing impairment, remains elusive. In this study, using molecular dynamics (MD) simulations, we showed that detached inner-wall N-terminal "plugs" aggregated to reduce the channel ion flow in a highly prevalent V37I variant in humans. To examine the predictive ability of the computational platform, an artificial mutant, V37M, of which the effect was previously unknown in hearing loss, was created. Microsecond simulations showed that homo-hexameric V37M Cx26 hemichannels had an abnormal affinity between the inner edge and N-termini to block the narrower side of the cone-shaped Cx26, while the most stable hetero-hexameric channels did not. From the perspective of the conformational energetics of WT and variant Cx26 hexamers, we propose that unaffected carriers could result from a conformational predominance of the WT and pore-shrinkage-incapable hetero-hexamers, while mice with homozygous variants can only harbor an unstable and dysfunctional N-termini-blocking V37M homo-hexamer. Consistent with these predictions, homozygous V37M transgenic mice exhibited apparent hearing loss, but not their heterozygous counterparts, indicating a recessive inheritance mode. Reduced channel conductivity was found in Gjb2V37M/V37M outer sulcus and Claudius cells but not in Gjb2WT/WT cells. We view that the current computational platform could serve as an assessment tool for the pathogenesis and inheritance of GJB2-related hearing impairments and other diseases caused by connexin dysfunction.
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Hearing impairment is one of the most common sensory disorders in children, and targeted next-generation sequencing (NGS)-based genetic examinations can assist in its prognostication and management. In 2020, we developed a simplified 30-gene NGS panel from the original 214-gene NGS version based on Taiwanese genetic epidemiology data to increase the accessibility of NGS-based examinations. In this study, we evaluated the diagnostic performance of the 30-gene NGS panel and compared it with that of the original 214-gene NGS panel in patient subgroups with different clinical features. Data on the clinical features, genetic etiologies, audiological profiles, and outcomes were collected from 350 patients who underwent NGS-based genetic examinations for idiopathic bilateral sensorineural hearing impairment between 2020 and 2022. The overall diagnostic yield was 52%, with slight differences in genetic etiology between patients with different degrees of hearing impairment and ages of onset. No significant difference was found in the diagnostic yields between the two panels, regardless of clinical features, except for a lower detection rate of the 30-gene panel in the late-onset group. For patients with negative genetic results, where the causative variant is undetectable on current NGS-based methods, part of the negative results may be due to genes not covered by the panel or yet to be identified. In such cases, the hearing prognosis varies and may decline over time, necessitating appropriate follow-up and consultation. In conclusion, genetic etiologies can serve as references for refining targeted NGS panels with satisfactory diagnostic performance.
Assuntos
Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Criança , Humanos , Epidemiologia Molecular , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/genética , Surdez/genética , Perda Auditiva/diagnóstico , Perda Auditiva/epidemiologia , Perda Auditiva/genética , Testes Genéticos/métodosRESUMO
Recessive variants in GJB2 are the most important genetic cause of sensorineural hearing impairment (SNHI) worldwide. Phenotypes vary significantly in GJB2-related SNHI, even in patients with identical variants. For instance, patients homozygous for the GJB2 p.V37I variant, which is highly prevalent in the Asian populations, usually present with mild-to-moderate SNHI; yet severe-to-profound SNHI is occasionally observed in approximately 10% of p.V37I homozygotes. To investigate the genomic underpinnings of the phenotypic variability, we performed next-generation sequencing of GJB2 and other deafness genes in 63 p.V37I homozygotes with extreme phenotypic severities. We identified additional pathogenic variants of other deafness genes in 5 of the 35 patients with severe-to-profound SNHI. Furthermore, we conducted case-control association analyses for 30 unrelated p.V37I homozygotes with severe-to-profound SNHI against 28 p.V37I homozygotes with mild-to-moderate SNHI, and 120 population controls from the Taiwan Biobank. We found that the severe-to-profound group had a higher frequency of the crystallin lambda 1 (CRYL1) variant (rs14236), located upstream of GJB2, than the mild-to-moderate and Taiwan Biobank groups. Our results demonstrated that pathogenic variants in other deafness genes and a possible modifier, the CRYL1 rs14236 variant, may contribute to phenotypic variability in GJB2-realted SNHI, highlighting the importance of comprehensive genomic surveys to delineate the genotype-phenotype correlations.
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OBJECTIVE: Unilateral sensorineural hearing loss (USNHL) is a condition commonly encountered in otolaryngology clinics. However, its molecular pathogenesis remains unclear. This study aimed to investigate the genetic underpinnings of childhood USNHL and analyze the associated audiological features. STUDY DESIGN: Retrospective analysis of a prospectively recruited cohort. SETTING: Tertiary referral center. METHODS: We enrolled 38 children with USNHL between January 1, 2018, and December 31, 2021, and performed physical, audiological, imaging, and congenital cytomegalovirus (cCMV) examinations as well as genetic testing using next-generation sequencing (NGS) targeting 30 deafness genes. The audiological results were compared across different etiologies. RESULTS: Causative genetic variants were identified in 8 (21.1%) patients, including 5 with GJB2 variants, 2 with PAX3 variants, and 1 with the EDNRB variant. GJB2 variants were found to be associated with mild-to-moderate USNHL in various audiogram configurations, whereas PAX3 and EDNRB variants were associated with profound USNHL in flat audiogram configurations. In addition, whole-genome sequencing and extended NGS targeting 213 deafness genes were performed in 2 multiplex families compatible with autosomal recessive inheritance; yet no definite causative variants were identified. Cochlear nerve deficiency and cCMV infection were observed in 9 and 2, respectively, patients without definite genetic diagnoses. CONCLUSION: Genetic underpinnings can contribute to approximately 20% of childhood USNHL, and different genotypes are associated with various audiological features. These findings highlight the utility of genetic examinations in guiding the diagnosis, counseling, and treatment of USNHL in children.
Assuntos
Infecções por Citomegalovirus , Surdez , Perda Auditiva Neurossensorial , Perda Auditiva Unilateral , Perda Auditiva , Humanos , Criança , Estudos Retrospectivos , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva/complicações , Testes Genéticos , Infecções por Citomegalovirus/complicações , Surdez/genética , Perda Auditiva Unilateral/genéticaRESUMO
Cinnabar, a naturally occurring mercuric sulfide (HgS), has long been used in Chinese mineral medicine for more than 2000 years. Although mercury is well-known for its toxicity, whether cinnabar induces neurotoxicity, especially in infants and children, is unknown. The purpose of this study was to explore the neurotoxic effects of low-dose of cinnabar (10 mg/kg/day) on developing mice. The results revealed neurobehavioral defects in F1-C-Cin group, which were associated with Hg accumulation, increased NO(x) levels in whole blood, and Na(+)/K(+)-ATPase activities in brain tissues. F1- and F2-Cin-V groups were found to increase brain Hg contents and prominent neurobehavioral defects compared with F1-C-V group, suggesting that the fetal brain was more susceptible to irreversible effects for cinnabar-induced damage. Moreover, F1- and F2-Cin-Cin groups had severely neurobehavioral dysfunctions, closely correlated with the further alteration of NO(x) levels and Na(+)/K(+)-ATPase activities than F1- and F2-C-Cin groups. Effects in F2-Cin-Cin group were more significant than those in F1-Cin-Cin group. In conclusion, this study demonstrates that exposure to low-dose of cinnabar during the perinatal and developmental stages results in irreversible and severe injuries of the neurotoxicity in offspring, and NO(x) and Na(+)/K(+)-ATPase activities may exist potential and useful biomarkers for neurotoxicity-induced by low-doses of mercuric compounds.
Assuntos
Compostos de Mercúrio/administração & dosagem , Compostos de Mercúrio/toxicidade , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/patologia , Neurotoxinas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Animais Recém-Nascidos , Limiar Auditivo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Feminino , Audição/efeitos dos fármacos , Tamanho da Ninhada de Vivíparos , Locomoção/efeitos dos fármacos , Masculino , Mercúrio/sangue , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Sono/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Fatores de TempoRESUMO
Rhinosinusitis is common in patients with nasopharyngeal carcinoma (NPC). Our study aimed to explore the role of rhinosinusitis severity in NPC prognosis. Medical records and radiologic examinations of 90 patients with NPC at a single medical center from 2009−2016 were retrospectively analyzed. The Lund−Mackay (L−M) score was obtained for each patient before and after 6 months of treatment. Rhinosinusitis diagnosis was based on L−M scores of ≥4. L−M score differences were calculated as pre-treatment rhinosinusitis (PRRS) minus post-treatment rhinosinusitis (PSRS). L−M score difference was sub-grouped into "L−M scores > 0", "L−M scores = 0", and "L−M scores < 0". Clinical staging of our patients based on the American Joint Committee on Cancer 7th edition were: stage I in nine, stage II in seventeen, stage III in twenty-two, and stage IV in forty-two patients; twenty-seven (30%) patients had died. PRRS incidence was 34.4%, and PSRS was 36.7%. Median of L−M scores difference was 0 (−2.2). L−M score difference was an independent prognostic factor for the overall survival of patients with NPC (p < 0.05). Therefore, worsening rhinosinusitis was a prognostic factor for patients with NPC. Clinicians should consider NPC as a warning sign of poor prognosis during routine follow-ups.