RESUMEN
BACKGROUND: Mutations in MPZL2, the characteristic genetic etiology of autosomal recessive deafness loci 111 (DFNB111), cause non-syndromic and moderate sensorineural hearing loss. METHODS: In this study, we analyzed the phenotype and genotype of eight pedigrees consisting of 10 hearing loss patients with bi-allelic pathogenic or likely pathogenic variants in MPZL2. These patients were identified from a 3272 Chinese patient cohort who underwent genetic testing. RESULTS: Apart from symmetrical and moderate sensorineural hearing loss, the MPZL2-related phenotype was characterized by progressive hearing loss with variation in the onset age (congenital defect to onset at the young adult stage). We determined that in the Chinese population, the genetic load of MPZL2 defects was 0.24% (8/3272) in patients diagnosed with hearing loss and 7.02% (8/114) in patients diagnosed with hereditary moderate sensorineural hearing loss caused by STRC, OTOA, OTOG, OTOGL, TECTA, MPZL2 and others. Three known MPZL2 variants (c.220C > T (p.Gln74*), c.68delC (p.Pro23Leufs*2), c.463delG (p.Ala155Leufs*10)) and a novel start loss variant (c.3G > T (p.Met1?)) were identified. MPZL2 c.220C > T was identified as the hotspot variant in the Chinese population and even in East Asia compared with c.72delA (p.Ile24Metfs*22) in European and West Asia through allele frequency. CONCLUSIONS: We concluded that apart from moderate HL, progressive HL is another character of MPZL2-related HL. No specified variant was verified for the progression of HL, the penetrance and expressivity cannot be determined yet. A novel MPZL2 variant at the start codon was identified, enriching the variant spectrum of MPZL2. The hotspot variants of MPZL2 vary in different ethnicities. This study provides valuable data for the diagnosis, prognosis evaluation and genetic counseling of patients with moderate sensorineural hearing loss related to MPZL2.
Asunto(s)
Sordera , Pérdida Auditiva Sensorineural , Humanos , Adulto Joven , Pueblo Asiatico/genética , Moléculas de Adhesión Celular , China , Sordera/etnología , Sordera/genética , Pérdida Auditiva Sensorineural/etnología , Pérdida Auditiva Sensorineural/genética , Péptidos y Proteínas de Señalización Intercelular , Proteínas de la MembranaRESUMEN
Defects in the posttranscriptional modifications of mitochondrial tRNAs have been linked to human diseases, but their pathophysiology remains elusive. In this report, we investigated the molecular mechanism underlying a deafness-associated tRNAIle 4295A>G mutation affecting a highly conserved adenosine at position 37, 3' adjacent to the tRNA's anticodon. Primer extension and methylation activity assays revealed that the m.4295A>G mutation introduced a tRNA methyltransferase 5 (TRMT5)-catalyzed m1G37 modification of tRNAIle. Molecular dynamics simulations suggested that the m.4295A>G mutation affected tRNAIle structure and function, supported by increased melting temperature, conformational changes and instability of mutated tRNA. An in vitro processing experiment revealed that the m.4295A>G mutation reduced the 5' end processing efficiency of tRNAIle precursors, catalyzed by RNase P. We demonstrated that cybrid cell lines carrying the m.4295A>G mutation exhibited significant alterations in aminoacylation and steady-state levels of tRNAIle. The aberrant tRNA metabolism resulted in the impairment of mitochondrial translation, respiratory deficiency, decreasing membrane potentials and ATP production, increasing production of reactive oxygen species and promoting autophagy. These demonstrated the pleiotropic effects of m.4295A>G mutation on tRNAIle and mitochondrial functions. Our findings highlighted the essential role of deficient posttranscriptional modifications in the structure and function of tRNA and their pathogenic consequence of deafness.
Asunto(s)
Pérdida Auditiva Sensorineural/genética , Mutación Puntual , ARN de Transferencia de Isoleucina/genética , Adenosina Trifosfato/biosíntesis , Adulto , Proteínas Arqueales/metabolismo , Autofagia , Secuencia de Bases , Línea Celular , ADN Mitocondrial/genética , Etnicidad/genética , Femenino , Pleiotropía Genética , Pérdida Auditiva Sensorineural/etnología , Humanos , Isoleucina/metabolismo , Masculino , Herencia Materna , Potencial de la Membrana Mitocondrial , Methanocaldococcus/enzimología , Metilación , Persona de Mediana Edad , Mitocondrias/metabolismo , Simulación de Dinámica Molecular , Conformación de Ácido Nucleico , Fosforilación Oxidativa , Linaje , Biosíntesis de Proteínas , Procesamiento Postranscripcional del ARN , Proteínas Recombinantes/metabolismo , Aminoacilación de ARN de Transferencia , Adulto Joven , ARNt Metiltransferasas/metabolismoRESUMEN
We present detailed comparative analyses to assess population-level differences in patterns of genetic deafness between European/American and Japanese cohorts with non-syndromic hearing loss. One thousand eighty-three audiometric test results (921 European/American and 162 Japanese) from members of 168 families (48 European/American and 120 Japanese) with non-syndromic hearing loss secondary to pathogenic variants in one of three genes (KCNQ4, TECTA, WFS1) were studied. Audioprofile characteristics, specific mutation types, and protein domains were considered in the comparative analyses. Our findings support differences in audioprofiles driven by both mutation type (non-truncating vs. truncating) and ethnic background. The former finding confirms data that ascribe a phenotypic consequence to different mutation types in KCNQ4; the latter finding suggests that there are ethnic-specific effects (genetic and/or environmental) that impact gene-specific audioprofiles for TECTA and WFS1. Identifying the drivers of ethnic differences will refine our understanding of phenotype-genotype relationships and the biology of hearing and deafness.
Asunto(s)
Proteínas de la Matriz Extracelular/genética , Genotipo , Pérdida Auditiva Sensorineural/genética , Canales de Potasio KCNQ/genética , Proteínas de la Membrana/genética , Mutación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Audiometría , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Proteínas Ligadas a GPI/genética , Expresión Génica , Estudios de Asociación Genética , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/etnología , Pérdida Auditiva Sensorineural/fisiopatología , Humanos , Lactante , Recién Nacido , Japón , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Estados Unidos , Población BlancaRESUMEN
OBJECTIVES: The identification of gene mutations enables more appropriate genetic counseling and proper medical management for EVA patients. The purpose of this study was to validate the accuracy and sensitivity of our method for comprehensive mutation detection in EVA, and summarize these data to explore a more accurate and convenient genetic diagnosis method. METHODS: A multiplex PCR sequencing panel was designed to capture the exons of three known EVA-associated genes (SLC26A4, KCNJ10, and FOXI1), and NGS was conducted in 17 Chinese families with EVA. RESULTS: A total of 16 SLC26A4 variants were found in 21 probands with bilateral EVA, including three novel variants (c.416G>A, c.823G>A and c.1027G>C), which were not reported in the dbSNP, gnomAD database, and ClinVar databases. One patient carried a FOXI1 variant (heterozygous, c.214C>A) and one patient carried a KCNJ10 variant (heterozygous, c.1054C>A), both of which were novel variants. Biallelic potential pathogenic variants were detected in 21/21patient samples, leading to a purported diagnostic rate of 100%. All results were verified by Sanger sequencing. CONCLUSION: This result supplemented the mutation spectrum of EVA, and supports that combined multiple PCR-targeted enrichment, and NGS is a valuable molecular diagnostic tool for EVA, and is suitable for clinical application.
Asunto(s)
Factores de Transcripción Forkhead/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación/genética , Canales de Potasio de Rectificación Interna/genética , Transportadores de Sulfato/genética , Acueducto Vestibular/anomalías , Adolescente , Pueblo Asiatico/genética , Niño , Preescolar , Análisis Mutacional de ADN , Exones , Femenino , Pérdida Auditiva Sensorineural/etnología , Heterocigoto , Humanos , Masculino , Proteínas de Transporte de Membrana/genética , Reacción en Cadena de la Polimerasa Multiplex , Adulto JovenRESUMEN
Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.
Asunto(s)
Pruebas Genéticas/normas , Pérdida Auditiva Sensorineural/genética , Mutación , Guías de Práctica Clínica como Asunto , Análisis de Secuencia de ADN/normas , Adolescente , Adulto , Anciano , Pueblo Asiatico/genética , Niño , Preescolar , Femenino , Pruebas Genéticas/métodos , Adhesión a Directriz , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/etnología , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN/métodosRESUMEN
OBJECTIVES: This study uses a new approach for classifying the human ethnicity according to the auditory brain responses (electroencephalography [EEG] signals) with a high level of accuracy. Moreover, the study presents three different algorithms used to classify the human ethnicity using auditory brain responses. The algorithms were tested on Malays and Chinese as a case study. MATERIALS AND METHODS: The EEG signal was used as a brain response signal, which was evoked by two auditory stimuli (Tones and Consonant Vowels stimulus). The study was carried out on Malaysians (Malay and Chinese) with normal hearing and with hearing loss. A ranking process for the subjects' EEG data and the nonlinear features was used to obtain the maximum classification accuracy. RESULTS: The study formulated the classification of Normal Hearing Ethnicity Index and Sensorineural Hearing Loss Ethnicity Index. These indices classified the human ethnicity according to brain auditory responses by using numerical values of response signal features. Three classification algorithms were used to verify the human ethnicity. Support Vector Machine (SVM) classified the human ethnicity with an accuracy of 90% in the cases of normal hearing and sensorineural hearing loss (SNHL); the SVM classified with an accuracy of 84%. CONCLUSION: The classification indices categorized or separated the human ethnicity in both hearing cases of normal hearing and SNHL with high accuracy. The SVM classifier provided a good accuracy in the classification of the auditory brain responses. The proposed indices might constitute valuable tools for the classification of the brain responses according to the human ethnicity.
Asunto(s)
Electroencefalografía/instrumentación , Potenciales Evocados Auditivos/fisiología , Pérdida Auditiva Sensorineural/fisiopatología , Pérdida Auditiva/fisiopatología , Estimulación Acústica/métodos , Adulto , Algoritmos , Audiometría de Tonos Puros/métodos , China/epidemiología , China/etnología , Etnicidad/estadística & datos numéricos , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/etnología , Humanos , Lenguaje , Malasia/etnología , Masculino , Persona de Mediana Edad , Ruido/efectos adversos , Percepción del Habla/fisiología , Máquina de Vectores de Soporte/normasRESUMEN
BACKGROUND: Deafness, autosomal recessive 77 (DFNB77) is a rare non-syndromic hearing loss (NSHL) worldwide, which is caused by deleterious variants within lipoxygenase homology domains 1 (LOXHD1). Here we identified that a novel missense variant of LOXHD1 was associated with NSHL in a Chinese family under consanguineous marriage. CASE PRESENTATION: A 28-year-old woman suffered a bilateral profound NSHL. Impedance audiometry, temporal bone computerized tomography (TBCT) scans and magnetic resonance imaging-inner ear hydrography (MRI-IEH) did not find any obvious abnormality of middle or inner ear. Routine genetic detection did not find pathogenic variants in common HL-associated genes. Therefore, we performed a whole-exome sequencing (WES) in this family. By trio-WES, co-segregation validation and bioinformatics analysis, we revealed that a novel homozygous variant in this patient, LOXHD1: c.5948C > T (p.S1983F), might be the pathogenic factor. Her parents (heterozygotes) and brother (wild-type) were asymptomatic. CONCLUSIONS: We successfully identified a novel variant of LOXHD1 associated with a rare NSHL from a Chinese family. Our finds highlight the effectiveness of trio-WES for molecular diagnosis of rare NHSL, and expand the genotypic spectrum of DFNB77.
Asunto(s)
Pueblo Asiatico/etnología , Proteínas Portadoras/genética , Secuenciación del Exoma/métodos , Pérdida Auditiva Sensorineural/genética , Mutación Missense , Adulto , Pueblo Asiatico/genética , Consanguinidad , Femenino , Pérdida Auditiva Sensorineural/etnología , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
Abstract Introduction: In different parts of the world, mutations in the GJB2 gene are associated with nonsyndromic hearing loss, and the homozygous 35delG mutation (p.Gly12Valfs*2) is a major cause of hereditary hearing loss. However, the 35delG mutation is not equally prevalent across ethnicities, making it important to study other mutations, especially in multiethnic countries such as Brazil. Objective: This study aimed to identify different mutations in the GJB2 gene in patients with severe to profound nonsyndromic sensorineural hearing loss of putative genetic origin, and who were negative or heterozygote for the 35delG mutation. Methods: Observational study that analyzed 100 ethnically characterized Brazilian patients with nonsyndromic severe to profound sensorineural hearing loss, who were negative or heterozygote for the 35delG mutation. GJB2 mutations were detected by DNA-based sequencing in this population. Participants' ethnicities were identified as Latin European, Non-Latin European, Jewish, Native, Turkish, Afro-American, Asian and Others. Results: Sixteen participants were heterozygote for the 35delG mutation; 14 participants, including three 35delG heterozygote's, had nine different alterations in the GJB2 gene. One variant, p.Ser199Glnfs*9, detected in two participants, was previously unreported. Three variants were pathogenic (p.Trp172*, p.Val167Met, and p.Arg75Trp), two were non-pathogenic (p.Val27Ile and p.Ile196Thr), and three variants were indeterminate (p.Met34Thr, p.Arg127Leu, and p.Lys168Arg). Three cases of compound heterozygosity were detected: p.[(Gly12Valfs*2)];[(Trp172*)], p.[(Gly12Valfs*2)](;)[(Met34Thr)], and p.[(Gly12Valfs*2)(;)[(Ser199Glnfs*9)]). Conclusion: This study detected previously unclassified variants and one case of previously unreported compound heterozygosity.
Resumo Introdução: Em diferentes partes do mundo, mutações do gene GJB2 estão associadas a perda auditiva não sindrômica e a mutação homozigótica 35delG (p.Gly12Valfs*2) é uma das principais causas de perda auditiva hereditária. No entanto, a mutação 35delG não é igualmente prevalente em todas as etnias, faz com que seja importante estudar outras mutações, especialmente em países multiétnicos, como o Brasil. Objetivo: Identificar diferentes mutações no gene GJB2 em pacientes com perda auditiva neurossensorial grave ou profunda não sindrômica de origem genética putativa e negativos ou heterozigotos para a mutação 35delG. Método: Estudo observacional que analisou 100 pacientes brasileiros caracterizados etnicamente, com perda auditiva neurossensorial grave ou profunda não sindrômica, negativos ou heterozigotos para a mutação 35delG. As mutações de GJB2 foram detectadas por sequenciamento baseado no DNA nessa população. As etnias dos participantes foram identificadas como latino-europeia, não latino-europeia, judaica, nativa, turca, negra, asiática e outras. Resultados: Dezesseis participantes eram heterozigotos para a mutação 35delG e 14, incluindo três heterozigotos para 35delG, apresentaram nove alterações no gene GJB2. Uma variante, p.Ser199Glnfs*9, detectada em dois participantes, não havia sido relatada anteriormente. Três variantes eram patogênicas (p.Trp172*, p.Val167Met, e p.Arg75Trp), duas não patogênicas (p.Val27Ile e p.Ile196Thr) e três indeterminadas (p.Met34Thr, p.Arg127Leu, e p.Lys168Arg). Três casos de heterozigosidade composta foram detectados: p.[(Gly12Valfs*2)];[(Trp172*)], p.[(Gly12Valfs*2)](;)[(Met34Thr)], e p.[(Gly12Valfs*2)(;)[(Ser199Glnfs*9)]). Conclusão: Este estudo detectou variantes não classificadas anteriormente e um caso de heterozigosidade composta ainda não relatada.
Asunto(s)
Humanos , Masculino , Femenino , Preescolar , Niño , Adolescente , Adulto , Persona de Mediana Edad , Adulto Joven , Conexinas/genética , Pérdida Auditiva Sensorineural/etnología , Pérdida Auditiva Sensorineural/genética , Mutación , Índice de Severidad de la Enfermedad , Brasil/etnología , Sordera/etnología , Sordera/genética , Frecuencia de los Genes , Pérdida Auditiva Sensorineural/congénitoRESUMEN
The present study investigated oral personal narratives elicited from Arabic speaking adolescents with and without hearing loss. Analyses focused on macrostructure, microstructure, and Modern Standard Arabic (MSA). For macrostructure, narratives were examined for structural components (abstract, orientation, complication, evaluation, resolution, and coda) and narrative patterns: classic (a high point followed by a resolution), high point ending, chronological, and leap frogging (jumps from one event to another). Microstructure included morpho-syntactic errors and complex sentences. MSA features were lexis and syntax. The narratives of adolescents with hearing loss tended to lack an evaluation component (expressing the narrator's perspective), contained more morpho-syntactic errors, fewer complex sentences, and fewer expressions of MSA than narratives of their hearing peers. Findings are discussed in terms of dissociation between macrostructure and microstructure in an attempt to shed light on those features of narrative which might benefit clinicians and educators working with Arabic speaking adolescents with hearing loss.
Asunto(s)
Pérdida Auditiva Sensorineural/psicología , Narración , Habla/fisiología , Adolescente , Árabes , Niño , Implantes Cocleares , Femenino , Audífonos , Pérdida Auditiva Sensorineural/etnología , Humanos , Israel , Lenguaje , Desarrollo del Lenguaje , Masculino , Lengua de SignosRESUMEN
OBJECTIVE: To examine the prevalence of ultrarapid metabolizers of codeine among children in an ethnically diverse urban community. STUDY DESIGN: Cross-sectional study. SETTING: A tertiary care academic children's hospital in the Bronx, New York. SUBJECTS AND METHODS: In total, 256 children with nonsyndromic congenital sensorineural hearing loss were analyzed. DNA was assessed for 63 previously described single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs) known to alter the function and expression of the CYP2D6 gene primarily responsible for codeine metabolism. The rate of CYP2D6 metabolism was predicted based on participants' haplotype. RESULTS: Ethnic distribution in the study subjects paralleled recent local census data, with the largest portion (115 children, 45.8%) identified as Hispanic or Latino. A total of 154 children (80.6%) had a haplotype that corresponds to extensive codeine metabolism, 18 children (9.42%) were identified as ultrarapid metabolizers (UMs), and 16 children (8.37%) were intermediate metabolizers. Only 3 children in our cohort (1.57%) were poor metabolizers. Patients identifying as Caucasian or Hispanic had an elevated incidence of UMs (11.3% and 11.2%, respectively) with extensive variability within subpopulations. CONCLUSIONS: The clinically significant rate of ultrarapid metabolizers reinforces safety concerns regarding the use of codeine and related opiates. A patient-targeted approach using pharmacogenomics may mitigate adverse effects by individualizing the selection and dosing of these analgesics.
Asunto(s)
Analgésicos Opioides/metabolismo , Codeína/metabolismo , Citocromo P-450 CYP2D6/genética , Etnicidad/genética , Población Urbana/estadística & datos numéricos , Población Blanca/genética , Niño , Estudios Transversales , Sordera/etnología , Sordera/genética , Femenino , Genotipo , Pérdida Auditiva Sensorineural/etnología , Pérdida Auditiva Sensorineural/genética , Humanos , Masculino , Polimorfismo Genético/genética , PrevalenciaRESUMEN
INTRODUCTION: In different parts of the world, mutations in the GJB2 gene are associated with nonsyndromic hearing loss, and the homozygous 35delG mutation (p.Gly12Valfs*2) is a major cause of hereditary hearing loss. However, the 35delG mutation is not equally prevalent across ethnicities, making it important to study other mutations, especially in multiethnic countries such as Brazil. OBJECTIVE: This study aimed to identify different mutations in the GJB2 gene in patients with severe to profound nonsyndromic sensorineural hearing loss of putative genetic origin, and who were negative or heterozygote for the 35delG mutation. METHODS: Observational study that analyzed 100 ethnically characterized Brazilian patients with nonsyndromic severe to profound sensorineural hearing loss, who were negative or heterozygote for the 35delG mutation. GJB2 mutations were detected by DNA-based sequencing in this population. Participants' ethnicities were identified as Latin European, Non-Latin European, Jewish, Native, Turkish, Afro-American, Asian and Others. RESULTS: Sixteen participants were heterozygote for the 35delG mutation; 14 participants, including three 35delG heterozygote's, had nine different alterations in the GJB2 gene. One variant, p.Ser199Glnfs*9, detected in two participants, was previously unreported. Three variants were pathogenic (p.Trp172*, p.Val167Met, and p.Arg75Trp), two were non-pathogenic (p.Val27Ile and p.Ile196Thr), and three variants were indeterminate (p.Met34Thr, p.Arg127Leu, and p.Lys168Arg). Three cases of compound heterozygosity were detected: p.[(Gly12Valfs*2)];[(Trp172*)], p.[(Gly12Valfs*2)](;)[(Met34Thr)], and p.[(Gly12Valfs*2)(;)[(Ser199Glnfs*9)]). CONCLUSION: This study detected previously unclassified variants and one case of previously unreported compound heterozygosity.
Asunto(s)
Conexinas/genética , Pérdida Auditiva Sensorineural/etnología , Pérdida Auditiva Sensorineural/genética , Mutación , Adolescente , Adulto , Brasil/etnología , Niño , Preescolar , Conexina 26 , Sordera/etnología , Sordera/genética , Femenino , Frecuencia de los Genes , Pérdida Auditiva Sensorineural/congénito , Humanos , Lactante , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Dwarfism is a common severe growth disorder, but the etiology is unclear in the majority of cases. Recombinant human growth hormone may be a treatment option, but it has limited efficacy. The currently known laboratory assays do not meet the precision requirements for clinical diagnosis. Here, we have constructed a targeted next-generation sequencing (NGS) panel of selected genes that are suspected to be associated with dwarfism for genetic screening. METHODS: Genetic screening of 91 children with short stature of unknown etiology was performed with the help of the NGS panel. All the coding regions and exon-intron boundaries of 166 genes were included in the panel. To clarify the pathogenicity of these mutations, their clinical data were reviewed and analyzed. RESULTS: The assay identified p.A72G, p.I282V, and p.P491S variants of the PTPN11 gene and a p.I437T variant of the SOS1 gene in 4 cases with Noonan syndrome. A frameshift mutation (p.D2407fs) of the ACAN gene was identified in a case of idiopathic short stature with moderately advanced bone age. A p.R904C variant of the COL2A1 gene was found in a patient, who was accordingly diagnosed with Stickler syndrome. Severe short stature without limb deformity was associated with a p.G11A variant of HOXD13. In addition, we evaluated evidence that a p.D401N variant of the COMP gene may cause multiple epiphyseal dysplasia. CONCLUSIONS: Our findings suggest that syndromes, particularly Noonan syndrome, may be overlooked due to atypical clinical features. This gene panel has been verified to be effective for the rapid screening of genetic etiologies associated with short stature and for guiding precision medicine-based clinical management.
Asunto(s)
Artritis/genética , Enfermedades del Tejido Conjuntivo/genética , Enanismo/genética , Pérdida Auditiva Sensorineural/genética , Mutación , Síndrome de Noonan/genética , Osteocondrodisplasias/genética , Desprendimiento de Retina/genética , Adolescente , Agrecanos/genética , Artritis/diagnóstico , Artritis/etnología , Artritis/patología , Pueblo Asiatico , Proteína de la Matriz Oligomérica del Cartílago/genética , Niño , Preescolar , Colágeno Tipo II/genética , Enfermedades del Tejido Conjuntivo/diagnóstico , Enfermedades del Tejido Conjuntivo/etnología , Enfermedades del Tejido Conjuntivo/patología , Enanismo/diagnóstico , Enanismo/etnología , Enanismo/patología , Femenino , Expresión Génica , Pruebas Genéticas/métodos , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/etnología , Pérdida Auditiva Sensorineural/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de Homeodominio/genética , Humanos , Masculino , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/etnología , Síndrome de Noonan/patología , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/etnología , Osteocondrodisplasias/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/etnología , Desprendimiento de Retina/patología , Proteína SOS1/genética , Factores de Transcripción/genéticaRESUMEN
The autosomal recessive non-syndromic hearing loss (ARNSHL) can be associated with variants in solute carrier family 26, member 4 (SLC26A4) gene and is the second most common cause of ARNSHL worldwide. Therefore, this study aims to determine the contribution of the SLC26A4 genotype in the hearing loss (HL) of 40 ARNSHL pedigrees in Iran. A cohort of the 40 Iranian pedigrees with ARNSHL, having no mutation in the GJB2 gene, was selected. The linkage analysis with five short tandem repeat (STR) markers linked to SLC26A4 was performed for the 40 ARNSHL pedigrees. Then, two out of the 40 pedigrees with ARNSHL that linked to DFNB4 locus were further screened to determine the variants in all exons of SLC26A4 gene by direct DNA sequencing. The 21 exons of SCL26A4 were analyzed for the two pedigrees. A known variant (c.716T>A homozygote), it is the first reported incidence in Iran, a novel variant (c.493A>C homozygote) were detected in the two pedigrees and pathogenesis of c.493A>C confirmed in this study with review 100 hearing ethnically matched controls by PCR-RFLP analysis. The present study suggests that the SLC26A4 gene plays a crucial role in the HL occurring in Iranian pedigrees. Also, the results probably support the specificity and unique spectrum of SLC26A4 variants among Iranian HL patients. Molecular study of SLC26A4 gene may lead to elucidation of the profile of the population-specific variants which has importance in diagnostics of HL.
Asunto(s)
Pérdida Auditiva Sensorineural/genética , Mutación/genética , Linaje , Transportadores de Sulfato/genética , Adulto , Niño , Estudios de Cohortes , Femenino , Ligamiento Genético , Pérdida Auditiva Sensorineural/etnología , Humanos , Irán , MasculinoRESUMEN
BACKGROUND/AIMS: Thiamine-responsive megaloblastic anemia syndrome is a rare autosomal recessive disorder resulting from mutations in SLC19A2, and is mainly characterized by megaloblastic anemia, diabetes, and progressive sensorineural hearing loss. METHODS: We study a Chinese Zhuang ethnicity family with thiamine-responsive megaloblastic anemia. The proband of the study presented with anemia and diabetes, similar to his late brother, as well as visual impairment. All clinical manifestations were corrected with thiamine (30 mg/d) supplementation for 1-3 months, except for visual impairment, which was irreversible. The presence of mutations in all exons and the flanking sequences of the SLC19A2 gene were analyzed in this family based on the proband's and his brother's clinical data. Computer analysis and prediction of the protein conformation of mutant THTR-1. The relative concentration of thiamine pyrophosphate in the proband's whole blood before and after initiation of thiamine supplement was measured by high performance liquid chromatography (HPLC). RESULTS: Gene sequencing showed a homozygous mutation in exon 6 of the SLC19A2 gene (c.1409insT) in the proband. His parents and sister were diagnosed as heterozygous carriers of the c.1409insT mutation. Computer simulation showed that the mutations caused a change in protein conformation. HPLC results suggested that the relative concentration of thiamine pyrophosphate in the proband's whole blood after thiamine supplement was significantly different (P=0.016) from that at baseline. CONCLUSIONS: This novel homozygous mutation (c.1409insT) caused the onset of thiamine-responsive megaloblastic anemia in the proband.
Asunto(s)
Anemia Megaloblástica/genética , Diabetes Mellitus/genética , Exones , Pérdida Auditiva Sensorineural/genética , Proteínas de Transporte de Membrana/genética , Mutación , Deficiencia de Tiamina/congénito , Anemia Megaloblástica/etnología , Anemia Megaloblástica/metabolismo , Anemia Megaloblástica/patología , Pueblo Asiatico , China/etnología , Diabetes Mellitus/etnología , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Femenino , Pérdida Auditiva Sensorineural/etnología , Pérdida Auditiva Sensorineural/metabolismo , Pérdida Auditiva Sensorineural/patología , Humanos , Lactante , Masculino , Proteínas de Transporte de Membrana/química , Proteínas de Transporte de Membrana/metabolismo , Deficiencia de Tiamina/etnología , Deficiencia de Tiamina/genética , Deficiencia de Tiamina/metabolismo , Deficiencia de Tiamina/patologíaRESUMEN
X-linked inheritance is very rare and is estimated to account for only 1-5% of all nonsyndromic hearing loss cases. We found a multiplex family from China segregating with X-linked nonsyndromic hearing loss. After exclusive analysis of 10 common variations of three hearing loss-related genes, GJB2, mtDNA12srRNA and SLC26A4, a novel truncated variant of SMPX, c.87dupA (p.Gly30Argfs*12) (NCBI ClinVar Submission ID: SUB3136126), was identified by whole-exome sequencing. This variant was co-segregated with hearing loss in the entire family and was absent in 576 unrelated ethnically and geographically matched controls. We also detected a single nucleotide variation in two male controls with normal hearing, SMPX c.55A>G (p.Asn19Asp), which has been annotated as a rare variant in the Single Nucleotide Polymorphism (dbSNP) (rs759552778) and Exome Aggregation Consortium (ExAC) databases. This study has enriched the mutation spectrum of the SMPX gene.
Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/genética , Pérdida Auditiva Sensorineural/genética , Proteínas Musculares/genética , Mutación , Adulto , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Bases de Datos Genéticas , Femenino , Pérdida Auditiva Sensorineural/etnología , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido Simple , Secuenciación del Exoma , Adulto JovenRESUMEN
PURPOSE: The Chinese Sound Test (Hung, Lin, Tsai, & Lee, 2016) has been recently developed as a modified version of the Ling Six-Sound Test (Ling, 2012). By incorporating Chinese speech sounds, this test should be able to estimate whether the listener can hear across the Chinese speech spectrum. To establish the clinical validity of the test, this study examined the relationship between the aided audiometric thresholds and the distance thresholds. METHOD: Sixty children with bilateral hearing aids were recruited. The aided sound-field thresholds at 250, 500, 1000, 2000, 4000, and 6000 Hz were compared with the distance thresholds of six sounds, /u, É, a, i, tÉÊ°, and s/, which encompass the entire Chinese speech frequency range from low to high. RESULTS: Partial correlation and stepwise regression analyses revealed that the Chinese testing sounds are frequency specific and that the audibility of each sound could be predicted by a specific frequency threshold. CONCLUSIONS: The results confirm the validity of the Chinese Sound Test, indicating that the testing sounds can be reliably used to assess the perception of frequency-specific information. Crucially, these data also demonstrate that the Chinese Sound Test is a useful tool to identify red flags of poor auditory access in daily environment to monitor device malfunctions and possible hearing fluctuations.
Asunto(s)
Audiometría/métodos , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/etnología , Fonética , Percepción del Habla/fisiología , Umbral Auditivo , Niño , China , Estudios de Cohortes , Femenino , Pérdida Auditiva Sensorineural/rehabilitación , Pruebas Auditivas/métodos , Humanos , Masculino , Valor Predictivo de las Pruebas , Análisis de Regresión , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES/HYPOTHESIS: Our objectives were to investigate pediatric cochlear implantation (PCI) across representative states within the United States and analyze any geographical differences in age, median household income, race, insurance, and total medical charges. STUDY DESIGN: Cross-sectional. METHODS: Data from children (aged 0.5-18 years) who received cochlear implantation surgery were collected from the 2011 State Ambulatory Surgery and Services Databases from California (CA), Florida (FL), Maryland (MD), New York (NY), and Kentucky (KY) as a part of the Healthcare Cost and Utilization Project. We performed data analysis using a combination of Kruskal-Wallis and Wilcoxon rank sum tests, as well as nominal logistic regression. RESULTS: Five hundred twelve cases of PCI were performed during 2011 across the five states. The overall mean and median age of implantation were 5.6 years and 4 years, respectively. There was no statistical difference in age of implantation across states (P = .85). However, there were statistical differences in primary payer (P < .001), median household income quartiles of patients who received an implant (P < .006), race (P < .001), and total median hospital charges for four of the states, with the exception of CA (P < .001). CONCLUSIONS: Age of PCI appears to be similar across the five states in cross-sectional analysis. Geographic variations in charges, payer, race, and median household income occur with statistical significance in PCI. Further analysis of contributing factors at each state level may help elucidate the root cause of these disparities and improve and justify a uniform approach to healthcare delivery and standards of care. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:954-958, 2018.
Asunto(s)
Implantación Coclear/estadística & datos numéricos , Honorarios y Precios/estadística & datos numéricos , Pérdida Auditiva Sensorineural/cirugía , Renta/estadística & datos numéricos , Seguro de Salud/economía , Grupos Raciales , Adolescente , Niño , Preescolar , Estudios Transversales , Femenino , Pérdida Auditiva Sensorineural/economía , Pérdida Auditiva Sensorineural/etnología , Humanos , Incidencia , Lactante , Masculino , Factores Socioeconómicos , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVES/HYPOTHESIS: To evaluate the relationships among measures of stroke risk and hearing in an African American cardiovascular study cohort. STUDY DESIGN: Prospective cohort study. METHODS: The relationships between stroke risk profiles and hearing of 1,107 individuals from a cohort of African Americans were assessed. Several different hearing pure-tone averages (PTAs) were constructed representing different frequency regions of hearing, namely PTA low, PTA mid, and PTA high. Stroke risk profiles were calculated using validated 10-year cardiovascular disease risk scores. Gamma regression analyses were performed for each PTA given as a continuous variable with change in stroke risk score. Logistic regression analyses, presented as odds ratios, were performed with hearing loss defined as any PTA >25 dB hearing level. Stratification models were analyzed for age quarterlies and among sex. RESULTS: Single unit increases of stroke risk percentage were found to be predictive of increases in all PTA threshold levels in gamma regression analyses for the overall pooled sample. The relationship was influenced by age, where fewer significant relationships were observed at higher ages. When analyzed with respect to stroke risk categories, using low risk as the reference group, there was found to be a significant association between stroke risk and hearing loss in the medium- and high-risk groups, with a stronger relationship in the high-risk group for all PTA threshold levels. CONCLUSIONS: This study provides evidence that stroke risk has a positive predictive relationship with hearing pure-tone threshold. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:1438-1444, 2018.
Asunto(s)
Pérdida Auditiva Sensorineural/etiología , Medición de Riesgo/métodos , Accidente Cerebrovascular/etiología , Adulto , Negro o Afroamericano , Anciano , Anciano de 80 o más Años , Audiometría de Tonos Puros/métodos , Umbral Auditivo , Estudios de Cohortes , Femenino , Audición/fisiología , Pérdida Auditiva Sensorineural/etnología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Accidente Cerebrovascular/etnología , Adulto JovenRESUMEN
Abstract Introduction: There is inconclusive evidence whether osteoporosis increases risk of hearing loss in current literature. Objective: We conducted this meta-analysis to determine whether there is an association between hearing loss and osteoporosis. Methods: This systematic review and meta-analysis was conducted from studies of MEDLINE, EMBASE, and LILACS. Osteoporosis was defined as having a bone mineral density with a T-score of less than −2.5 standard deviation. The outcome was hearing loss as assessed by audiometry or self-reported assessment. Random-effects model and pooled hazard ratio, risk ratio, or odds ratio of hearing loss with 95% confidence intervals were compared between normal bone mineral density and low bone mineral density or osteoporosis. Results: A total of 16 articles underwent full-length review. Overall, there was a statistically significant increased odds of hearing loss in the low bone mineral density or osteoporosis group with odds ratio of 1.20 (95% confidence intervals 1.01-1.42, p = 0.04, I 2 = 82%, Pheterogeneity = 0.01). However, the study from Helzner et al. reported significantly increase odds of hearing loss in the low bone mineral density in particular area and population included femoral neck of black men 1.37 (95% confidence intervals 1.07-1.76, p = 0.01) and total hip of black men 1.36 (95% confidence intervals 1.05-1.76, p = 0.02). Conclusion: Our study proposed the first meta-analysis that demonstrated a probable association between hearing loss and bone mineral density. Osteoporosis could be a risk factor in hearing loss and might play an important role in age-related hearing loss.
Abstract Introduction: There is inconclusive evidence whether osteoporosis increases risk of hearing loss in current literature. Objective: We conducted this meta-analysis to determine whether there is an association between hearing loss and osteoporosis. Methods: This systematic review and meta-analysis was conducted from studies of MEDLINE, EMBASE, and LILACS. Osteoporosis was defined as having a bone mineral density with a T-score of less than −2.5 standard deviation. The outcome was hearing loss as assessed by audiometry or self-reported assessment. Random-effects model and pooled hazard ratio, risk ratio, or odds ratio of hearing loss with 95% confidence intervals were compared between normal bone mineral density and low bone mineral density or osteoporosis. Results: A total of 16 articles underwent full-length review. Overall, there was a statistically significant increased odds of hearing loss in the low bone mineral density or osteoporosis group with odds ratio of 1.20 (95% confidence intervals 1.01-1.42, p = 0.04, I 2 = 82%, Pheterogeneity = 0.01). However, the study from Helzner et al. reported significantly increase odds of hearing loss in the low bone mineral density in particular area and population included femoral neck of black men 1.37 (95% confidence intervals 1.07-1.76, p = 0.01) and total hip of black men 1.36 (95% confidence intervals 1.05-1.76, p = 0.02). Conclusion: Our study proposed the first meta-analysis that demonstrated a probable association between hearing loss and bone mineral density. Osteoporosis could be a risk factor in hearing loss and might play an important role in age-related hearing loss.
Asunto(s)
Humanos , Masculino , Femenino , Osteoporosis/complicaciones , Perdida Auditiva Conductiva-Sensorineural Mixta/etiología , Pérdida Auditiva Conductiva/etiología , Pérdida Auditiva Sensorineural/etiología , Osteoporosis/etiología , Densidad Ósea/fisiología , Factores Sexuales , Factores de Riesgo , Factores de Edad , Perdida Auditiva Conductiva-Sensorineural Mixta/etnología , Pérdida Auditiva Conductiva/etnología , Pérdida Auditiva Sensorineural/etnologíaRESUMEN
The Saami are the only indigenous population in Europe and their traditional living area is northern Scandinavia. Hearing impairment (HI) among Saami has not been studied before. The objective was to investigate the presence and type of HI among Saami adults, aged 49-77 years (median age 61 years), living in northern Finland. In addition, the presence of self-reported hearing difficulties, difficulties to hear in background noise and tinnitus were studied. An epidemiological, cross-sectional study encompassing a structured interview, otological examination and audiometry was performed. Bilateral HI was present in 42.9% of men and 29.4% of women, when HI was defined as a pure tone average (PTA) of at least 20 dB hearing level (HL) or more at the frequencies of 0.5, 1, 2 and 4 kHz. In one or both ears (worse ear hearing level, WEHL0.5,1,2,4≥20 dB HL) HI was present in 61.8% of men and 42.2% of women. Sensorineural high frequency hearing impairment was found to be most common. Nearly half (46.9%) of the study subjects reported hearing problems and more than half (55.6%) reported difficulties in following conversation in background noise. Measured HI and subjective hearing difficulties are common among the Saami adults. The healthcare personnel working in this area should be aware of the hearing problems of the Saami population. ABBREVIATIONS: ARHI, Age-related hearing impairment; PTA, Pure tone average; HI, Hearing impairment; HL, Hearing level; BEHL, Better ear hearing level; WEHL, Worse ear hearing level; CI, Confidence interval.