Long-term auditory monitoring in children with Alport syndrome based on different degrees of renal injury / 临床耳鼻咽喉头颈外科杂志

Objective:To investigate long-term auditory changes and characteristics of Alport syndrome（AS） patients with different degrees of renal injury. Methods:Retrospectively analyzing clinical data of patients diagnosed AS from January 2007 to September 2022, including renal pathology, genetic detection and hearing examination. A long-term follow-up focusing on hearing and renal function was conducted. Results:This study included 70 AS patients, of which 33（25 males, 8 females, aged 3.4-27.8 years） were followed up, resulting in a loss rate of 52.9%.The follow-up period ranged from 1.1to 15.8 years, with 16 patients followed-up for over 10 years. During the follow-up, 10 patients presenting with hearing abnormalities at the time of diagnosis of AS had progressive hearing loss, and 3 patients with new hearing abnormalities were followed up, which appeared at 5-6 years of disease course. All of which were sensorineural deafness. While only 3 patients with hearing abnormalities among 13 patients received hearing aid intervention. Of these patients,7 developed end-stage renal disease（ESRD）, predominantly males （6/7）. The rate of long-term hearing loss was significantly different between ESRD group and non-ESRD group（P=0.013）. There was no correlation between the progression of renal disease and long-term hearing level（P>0.05）. kidney biopsies from 28 patients revealed varying degrees of podocyte lesion and uneven thickness of basement membrane. The severity of podocyte lesion was correlated with the rate of long-term hearing loss（P=0.048）, and there was no correlation with the severity of hearing loss（P>0.05）. Among 11 cases, theCOL4A5mutationwas most common （8 out of 11）, but there was no significant correlation between the mutation type and hearing phenotype（P>0.05）. Conclusion:AS patients exhibit progressive hearing loss with significant heterogeneity over the long-term.. THearing loss is more likely to occur 5-6 years into the disease course. Hearing abnormalities are closely related to renal disease status, kidney tissue pathology, and gene mutations, emphasizing the need for vigilant long-term hearing follow-up and early intervention.

Genetic and phenotypic analysis of MYO15A rare variants associated with autosomal recessive hearing loss / 临床耳鼻咽喉头颈外科杂志

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.

Splicing mutations of GSDME cause late-onset non-syndromic hearing loss / 临床耳鼻咽喉头颈外科杂志

Objective:To dentify the genetic and audiological characteristics of families affected by late-onset hearing loss due to GSDMEgene mutations, aiming to explore clinical characteristics and pathogenic mechanisms for providing genetic counseling and intervention guidance. Methods:Six families with late-onset hearing loss from the Chinese Deafness Genome Project were included. Audiological tests, including pure-tone audiometry, acoustic immittance, speech recognition scores, auditory brainstem response, and distortion product otoacoustic emission, were applied to evaluate the hearing levels of patients. Combining with medical history and physical examination to analyze the phenotypic differences between the probands and their family members. Next-generation sequencing was used to identify pathogenic genes in probands, and validations were performed on their relatives by Sanger sequencing. Pathogenicity analysis was performed according to the American College of Medical Genetics and Genomics Guidelines. Meanwhile, the pathogenic mechanisms of GSDME-related hearing loss were explored combining with domestic and international research progress. Results:Among the six families with late-onset hearing loss, a total of 30 individuals performed hearing loss. The onset of hearing loss in these families ranged from 10 to 50 years（mean age: 27.88±9.74 years）. In the study, four splicing mutations of the GSDME were identified, including two novel variants: c. 991－7C>G and c. 1183+1G>T. Significantly, the c. 991－7C>G was a de novo variant. The others were previously reported variants: c. 991-1G>C and c. 991-15_991-13del, the latter was identified in three families. Genotype-phenotype correlation analysis revealed that probands with the c. 991－7C>G and c. 1183+1G>T performed a predominantly high-frequency hearing loss. The three families carrying the same mutation exhibited varying degrees of hearing loss, with an annual rate of hearing deterioration exceeding 0.94 dB HL/year. Furthermore, follow-up of interventions showed that four of six probands received intervention（66.67%）, but the results of intervention varied. Conclusion:The study analyzed six families with late-onset non-syndromic hearing loss linked to GSDME mutations, identifying four splicing variants. Notably, c. 991－7C>G is the first reported de novo variant of GSDME globally. Audiological analysis revealed that the age of onset generally exceeded 10 years,with variable effectiveness of interventions.

Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations / 中华耳鼻咽喉头颈外科杂志

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.

Analysis of genotypes on 850 newborns with SLC26A4 single-allele mutation and the phenotypes of those with second variant / 中华耳鼻咽喉头颈外科杂志

Objective: To clarify the phenotypes of the newborns with SLC26A4 single-allele mutation in deafness genetic screening and second variant; to analyze the SLC26A4 genotype and hearing phenotype. Methods: 850 newborns born in Beijing from April 2015 to December 2019 were included and there were 468 males and 382 females. They received genetic deafness screening for 9 or 15 variants, with the result of SLC26A4 single-allele mutation. Firstly, three step deafness gene sequencing was adopted in this work, i.e., the first step was "SLC26A4 gene whole exons and splice sites" sequencing; the second step was "SLC26A4 gene promoter, FOXI1 gene and KCNJ10 gene whole exons" sequencing; and the third step was detection for "SLC26A4 gene copy number variation". Secondly, we collected the results of newborn hearing screening for all patients with the second mutation found in the three step test, and conducted audiological examinations, such as acoustic immittance, auditory brainstem response and auditory steady state response. Thirdly, for novel/VUS mutations, we searched the international deafness gene database or software, such as DVD, ClinVar and Mutation Taster, to predict the pathogenicity of mutations according to the ACMG guideline. Lastly, we analyzed the relationship between genotype and phenotype of newborns with SLC26A4 single allele mutation. Results: Among 850 cases, the median age of diagnosis was 4 months. In the first step, 850 cases were sequenced. A total of 32 cases (3.76%, 32/850) of a second variants were detected, including 18 cases (2.12%, 18/850) with identified pathogenic variants; 832 cases were sequenced and 8 cases of KCNJ10 gene missense variants were detected among the second step. No missense mutations in the FOXI1 gene and abnormal SLC26A4 gene promoter were detected; the third step sequencing results were all negative. Genotypes and hearing phenotypes included 18 cases combined with the second clear pathogenic variant, 16 cases (16/18) referred newborn hearing screening and 2 cases (2/18) passed in both ears; degree of hearing loss consisted of 18 profound ears (18/36), 13 severe ears (13/36) and 5 moderate ears (5/36); audiogram patterns comprised 17 high frequency drop ears (17/36), 14 flat ears (14/36), 3 undistinguished ears (3/36), and 2 U shaped ears (2/36); 11 cases underwent imaging examination, all of which were bilateral enlarged vestibular aqueduct. As for 22 cases of other genotypes, all passed neonatal hearing screening and the hearing diagnosis was normal, including 9 cases with VUS or possibly novel benign variants, 8 cases with KCNJ10 double gene heterozygous variants, and 5 cases with double heterozygous variants. Conclusions: The probability of individuals with SLC26A4 single-allele variant who merge with a second pathogenic variant is 2.12%, all of which are SNV, which can provide scientific basis for the genetic diagnosis and genetic counseling of SLC26A4 variants. Those who have merged with second pathogenic variant are all diagnosed with sensorineural hearing loss. Patients with KCNJ10 gene mutations do not manifest hearing loss during the infancy, suggesting the need for further follow-up.

The clinical phenotype and gene analysis of syndromic deafness with PTPN11 gene mutation / 中华耳鼻咽喉头颈外科杂志

Objective: To analyze the clinical phenotype and screen the genetic mutations of hereditary deafness in three deaf families to clarify their molecular biology etiology. Methods: From January 2019 to January 2020, three deaf children and family members were collected for medical history, physical examination, audiology evaluation, electrocardiogram and cardiac color Doppler ultrasound, temporal bone CT examination, and peripheral blood DNA was obtained for high-throughput sequencing of deafness genes. Sanger sequencing was performed to verify the variant sites among family members. The pathogenicity of the variants was evaluated according to the American College of Medical Genetics and Genomics. Results: The probands in the three families had deafness phenotypes. In family 1, proband had multiple lentigines, special facial features, growth retardation, pectus carinatum, abnormal skin elasticity, cryptorchidism and other manifestations. In family 2, proband had special facial features, growth retardation and abnormal heart, and the proband in family 3 had growth retardation and abnormal electrocardiogram. Genetic testing of three families detected three heterozygous mutations in the PTPN11 gene: c.1391G>C (p.Gly464Ala), c.1510A>G (p.Met504Val), c.1502G>A (p.Arg501Lys). All three sites were missense mutations, and the mutation sites were highly conserved among multiple homologous species. Based on clinical manifestations and genetic test results, proband 1 was diagnosed with multiple lentigines Noonan syndrome, and probands 2 and 3 were diagnosed with Noonan syndrome. Conclusion: Missense mutations in the PTPN11 gene may be the cause of the disease in the three deaf families. This study enriches the clinical phenotype and mutation spectrum of the PTPN11 gene in the Chinese population.

Association between cytogenetic alteration and the audiometric profile of individuals with Turner syndrome / Relação entre alteração citogenética e o perfil audiométrico de indivíduos com síndrome de Turner

Abstract Introduction: Turner syndrome is a frequent genetic disorder that affects female individuals and covers a large phenotypic variability. Scientific literature suggests an association between hearing loss and Turner syndrome, but it remains a controversial topic. Objective: To associate the cytogenetic alteration with the audiometric profile of individuals with Turner syndrome. Methods: Cross-sectional study, with a hospital-based, convenience sample. Patients diagnosed with Turner syndrome were included and those with difficulty understanding the audiometry and/or other associated syndromes were excluded. The participants were studied with pure tone audiometry. Results: Of the 65 patients included, 36.9% had X chromosome monosomy and 63.0% had other alterations. Regarding the audiometry, 64.6% had normal thresholds and 35.3% had hearing impairment. Of these, 30.4% had hybrid hearing loss, 26.0% alteration at 6 and/or 8 kHz, 17.3% had conductive hearing loss, 13.0% sensorineural loss and 13.0% had mixed hearing loss. We observed that the mild degree was the most frequent one. There was no statistically significant association between the cytogenetic type of Turner syndrome and the presence or absence of hearing loss, or with the type and degree of hearing loss. Conclusion: The cytogenetic alteration in Turner syndrome was not associated with the audiometric profile, which showed variability regarding the type and degree of hearing loss.

Resumo Introdução: A síndrome de Turner é uma alteração frequente e genética que acomete indivíduos do sexo feminino e abrange grande variabilidade fenotípica. A literatura científica sugere uma relação entre perda auditiva e síndrome de Turner, porém ainda é um tema controverso. Objetivo: Relacionar a alteração citogenética com o perfil audiométrico de indivíduos com síndrome de Turner. Método: Estudo transversal, com amostra de conveniência, de base hospitalar. Foram incluídas pacientes com diagnóstico de síndrome de Turner e excluídas as com dificuldade para compreender a audiometria e/ou outras síndromes associadas. As participantes foram submetidas à audiometria tonal. Resultados: Das 65 pacientes incluídas, 36,9% apresentaram monossomia do cromossomo X e 63,0%, outras alterações. Com relação à audiometria, 64,6% apresentaram limiares dentro da normalidade e 35,3% alteração auditiva. Dessas, 30,4% apresentaram perda auditiva híbrida, 26,0% alteração em 6 e/ou 8 KHz; 17,3% perda auditiva condutiva, 13,0% perda neurossensorial e 13,0% perda auditiva mista. Observamos que o grau leve foi o mais frequente. Não foi observada associação estatiscamente significativa entre o tipo citogenético da síndrome de Turner e a presença ou não perda auditiva, ou com o tipo e grau de perda auditiva. Conclusão: A alteração citogenética na síndrome de Turner não teve associação com o perfil audiométrico, o qual apresentou variabilidade quanto ao tipo e grau da perda auditiva.

Analysis of result of gene screening of neonatal deafness in Huizhou and surrounding urban areas / 中华医学遗传学杂志

OBJECTIVE@#To detect common pathogenic variants associated with congenital deafness among neonates from Huizhou and surrounding areas and discuss its implications.@*METHODS@#Thirteen hot-spot mutations in four most common pathogenic genes were screened among 20 934 neonates from March 2017 to December 2019.@*RESULTS@#In total 760 neonates were found to carry common pathogenic variants (3.63%). Sixty two neonates have carried homozygous/compound heterozygous variants or homoplasmy/heteroplasmy mutations of mtDNA (0.29%). Further analysis of five abnormal cases revealed that 3 of them have carried compound heterozygous mutations of GJB2 gene, and 2 were due to compound heterozygous variants of the CDH23 gene.@*CONCLUSION@#Genetic testing has a great clinical significance for the prevention and reduction of congenital hearing loss, but the scope needs to be updated and redefined by removing mutation sites with a very low rate, adding new significant sites, and improvement of the technical strategies.

New SNP variants of MARVELD2 (DFNB49) associated with non-syndromic hearing loss in Chinese population / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Non-syndromic hearing loss (NSHL) is a common defect in humans. Variants of MARVELD2 at the DFNB49 locus have been shown to cause bilateral, moderate to profound NSHL. However, the role of MARVELD2 in NSHL susceptibility in the Chinese population has not been studied. Here we conducted a case-control study in an eastern Chinese population to profile the spectrum and frequency of MARVELD2 variants, as well as the association of MARVELD2 gene variants with NSHL. Our results showed that variants identified in the Chinese population are significantly different from those reported in Slovak, Hungarian, and Czech Roma, as well as Pakistani families. We identified 11 variants in a cohort of 283 NSHL cases. Through Sanger sequencing and bioinformatics analysis, we found that c.730G>A variant has detrimental effects in the eastern Chinese population, and may have relatively high correlation with NSHL pathogenicity.

Comportamiento de la hipoacusia no sindrómica en una familia del municipio de Urbano Noris. Holguín / Behavior of non-syndromic hearing loss in a family in the municipality of Urbano Noris. Holguín

Fundamento: La hipoacusia hereditaria de causa no sindrómica se presenta frecuentemente en los humanos. Los estudios clínicos y genéticos han permitido conocer mutaciones asociadas a múltiples genes que producen esta enfermedad. Se considera importante saber las características de la presentación de la hipoacusia en cada familia, lo que determinaría su patrón de herencia y así permitiría poder realizar un adecuado asesoramiento genético en estas familias. Objetivo: Describir las características de la hipoacusia no sindrómica en los afectados de la esta familia estudiada. Metodología: Se realizó un estudio de serie de casos en una familia del municipio de Urbano Noris, provincia Holguín. El universo de estudio estuvo constituido por los 45 integrantes de la familia, la muestra quedó formada por los 24 enfermos con hipoacusia. Se les solicitó consentimiento informado, se realizó examen físico audiológico a todos los participantes, se logró definir y clasificar los pacientes con el grado de hipoacusia. Resultados: El grupo de edades que predominó estuvo comprendido entre 16 y 25 años con 7 pacientes; el mayor número de afectados del sexo masculino fue 13 (54,16 %). La hipoacusia moderada se observó en 11 pacientes (45,83 %), seguida por la severa en 8 pacientes (33,33 %). Se determinó la hipoacusia no sindrómica en esta familia con un patrón de herencia autonómica dominante. Conclusiones: Prevaleció el sexo masculino y la hipoacusia moderada. Se corroboró la gran heterogeneidad clínica descrita para esta enfermedad. Se confirmó la expresividad variable en esta familia.

Background: hereditary hearing loss of non-syndromic cause frequently occurs in humans. Clinical and genetic studies have made possible to know mutations associated with multiple genes that produce this disease. It is considered important to know the characteristics of the presentation of hearing loss in each family, determining their inheritance pattern that would allow adequate genetic counseling in these families. Objective: to describe the characteristics of non-syndromic hearing loss in the affected of this studied family. Methodology: A retrospective descriptive study was carried out in a family from the municipality of Urbano Noris, Holguín province. The study universe consisted of the 45 members of the family; the sample was formed by the 24 patients with hearing loss. Informed consent was requested, audiological physical examination was performed in all participants, and patients were defined and classified with the degree of hearing loss. Results: the predominant age group was between 16 and 25 years old with 7 patients, the highest number of males affected, with 13 being (54.16 %). Moderate hearing loss prevailed with 11 patients for (45.83 %) followed by severe hearing loss with 8 patients for (33.33 %).Non-syndromic hearing loss was determined in this family with a dominant autonomic inheritance pattern. Conclusions: Prevalence of male gender and moderate hearing loss. The great clinical heterogeneity described for this disease was corroborated. The variable expressivity in this family was confirmed.

Caracterização demográfica, clínica e genética da deficiência auditiva na Bahia / Demographic and clinical characteristics and genetic hearing impairment in Bahia

Dados do censo demográfico brasileiro de 2010 demonstram que 5,5% da população baiana possui alguma dificuldade auditiva (DA) (IBGE, 2010). No entanto, dados mais detalhados sobre a DA no estado da Bahia são muito escassos. Por isso, tem-se como objetivo desse trabalho traçar o perfil dos pacientes encaminhados para concessão de aparelhos de amplificação sonora individual em uma unidade do SUS de referência estadual do estado da Bahia, analisando as diferentes variáveis: faixa etária, sexo, escolaridade, tipo e grau da perda auditiva, histórico familiar da DA, consanguinidade entre os pais e relato de fatores associados com a DA. Para isso foi realizado estudo observacional de corte transversal, com análise de 2.711 prontuários do setor de reabilitação auditiva Cepred no período de um ano, entre os anos 2012 e 2013. Foram identificados possíveis casos de etiologia genética, cuja base molecular foi investigada através da análise das mutações: c.35delG no gene GJB2 (rs80338939), as deleções del(GJB6-13S1830) e del (GJB6-D13S1854)...

Brazilian demographic census showed that 5.5% of Bahia's population has some hearing difficulty (HI) (IBGE, 2010). However, there are not detailed data about the HI in Bahia. So, present study objectived establish the profile of patients referred for granting individual sound amplification devices in a SUS unit of state of Bahia reference, analyzing the different variables: age, gender, education, type and degree of hearing loss, family history of AD, consanguinity between parents and account factors associated with AD. For that, it was conducted a one year observational cross-sectional study, for analysis of 2711 medical records of the hearing rehabilitation sector of the Cepred. According medical records it was possible suggest genetic etiology on some cases. The genetic etiology was confirmed molecularly. First, it was investigated four mutations: c.35delG GJB2 (rs80338939) gene, the deletion del (GJB6-13S1830) and del (GJB6-D13S1854)...

Relação entre perda auditiva e alterações genéticas em pacientes tratados de câncer na infância / Relations between hearing loss and genetic alterations in patients treated from cancer during childhood

A ototoxicidade é uma das sequelas do tratamento oncológico com uso de quimioterápicos derivados da platina cisplatina (CDDP) e carboplatina (CBDCA). Tal tratamento pode provocar a lesão do órgão periférico da audição acometendo a estria vascular e células ciliadas externas (CCE) do giro basal. A perda auditiva causada pela ototoxicidade é neurossensorial bilateral prejudicando inicialmente altas frequências e o seu uso contínuo pode acometer frequências ≤ 4 kHz prejudicando o reconhecimento de fala. Estudos recentes têm demonstrado uma associação entre algumas variantes genéticas e a toxicidade dos derivados da platina. O objetivo do nosso estudo foi identificar se há influência de fatores genéticos na perda auditiva encontrada em pacientes tratados de câncer na infância submetidos a quimioterápicos derivados da platina. Avaliamos a ocorrência de perda auditiva e sua associação com a dose de CDDP e CBDCA assim como, a associação entre a ototoxicidade e a presença das variantes MT-RNR1- m.1555A>G, GJB2-c.35delG, e GSTP1-c.313A>G. Material e Método: Foram selecionados pacientes que tiveram câncer na infância e estavam fora de tratamento por pelo menos cinco anos. Setenta e três pacientes preencheram os critérios e assinaram o termo de consentimento livre e esclarecido. Sessenta e um pacientes realizaram tratamento de risco para a audição com derivados da platina e 12 pacientes sem tratamento de risco para audição. Todos realizaram avaliação audiológica...

Ototoxicity is one of the adverse effects in the oncological treatment using chemotherapy with platin agents such cisplatin (CDDP) and/or carboplatin (CBDCA). Such treatment may lead to end organ lesions in the auditory system involving the stria vascularis and outer hair cells, mainly at the basal turn. Hearing loss caused by ototoxicity is bilateral, sensorineural affecting initially the high frequencies, but it may progress to frequencies below 4 kHz and compromise the speech recognition. Recent studies have demonstrated that the association of some genetic variants with the toxicity of platin agents. The aim of this study was to identify whether there is any influence of genetic factors on the hearing loss found in patients treated from cancer during childhood with platin agents. The occurrence of hearing loss and its association with the cisplatin and carboplatin dosages, as well as the presence of variants of A1555G in the mitochondrial gene MT-RNR1 (12S rRNA), 35delG in the GJB2 gene, and c.313A>G in the GSTP1 gene were evaluated. Material and Methods: Patients who had cancer during childhood, who were released from treatment for at least 5 years were selected. Seventy-three patients fullfilled the criteria and signed the...

Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene

GJB2 alleles containing two cis mutations have been rarely found in non-syndromic hearing loss. Herein, we present a Korean patient with non-syndromic hearing loss caused by the R75Q cis mutation with V37I, which arose de novo in the father and was inherited by the patient. Biochemical coupling and hemichannel permeability assays were performed after molecular cloning and transfection of HEK293T cells. Student's t-tests or analysis of variance followed by Tukey's multiple comparison test was used as statistical analysis. Biochemical coupling was significantly reduced in connexin 26 (Cx26)-R75Q- and Cx26-V37I-transfected cells, with greater extent in Cx26-R75Q and Cx26-R75Q+V37I cells. Interestingly, our patient and his father with the mutations had more residual hearing compared with patients with the dominant mutation alone. Although the difference in hemichannel activity between R75Q alone and R75Q in combination with V37I failed to reach significance, it is of note that there is a possibility that V37I located upstream of R75Q might have the ability to ameliorate R75Q expression. Our study emphasizes the importance of cis mutations with R75Q, as the gene effect of R75Q can be modulated depending on the type of additional mutation.

Síndrome de Jervell y Lange-Nielsen / Jervell and Lange-Nielsen Syndrome

El síndrome de Jervell y Lange-Nielsen es una forma poco frecuente de síndrome de QT largo. Su herencia es autosómica recesiva y se manifiesta con sordera neurosensorial. Revisamos el caso de una niña de 7 años implantada coclear bilateral. Tras un episodio sincopal se realiza el diagnóstico de síndrome de QT largo, el estudio genético confirma el diagnóstico. Recomendamos realizar electrocardiograma a todos los niños con hipoacusia severa con el objeto de descartar este síndrome.

The Jervell and Lange-Nielsen (JLNS) is an uncommon form of long QT syndrome. His inheritance is autosomal recessive and manifests as a sensorineural deafness. We review the case of a 7 year old girl bilateral cochlear implanted. After a syncope episode, a long QT syndrome was confirmed by genetic study. We recommend electrocardiogram (ECG) to all children with severe hearing loss in order to rule out this syndrome.

Audiological outcomes of cochlear implantation in Waardenburg Syndrome

The most relevant clinical symptom in Waardenburg syndrome is profound bilateral sensorioneural hearing loss. AIM: To characterize and describe hearing outcomes after cochlear implantation in patients with Waardenburg syndrome to improve preoperative expectations. METHOD: This was an observational and retrospective study of a series of cases. Children who were diagnosed with Waardenburg syndrome and who received a multichannel cochlear implant between March 1999 and July 2012 were included in the study. Intraoperative neural response telemetry, hearing evaluation, speech perception, and speech production data before and after surgery were assessed. RESULTS: During this period, 806 patients received a cochlear implant and 10 of these (1.2%) were diagnosed with Waardenburg syndrome. Eight of the children received a Nucleus 24® implant and 1 child and 1 adult received a DigiSonic SP implant. The mean age at implantation was 44 months among the children. The average duration of use of a cochlear implant at the time of the study was 43 months. Intraoperative neural responses were present in all cases. Patients who could use the speech processor effectively had a pure tone average of 31 dB in free-field conditions. In addition, the MUSS and MAIS questionnaires revealed improvements in speech perception and production. Four patients did not have a good outcome, which might have been associated with ineffective use of the speech processor. CONCLUSION: Despite the heterogeneity of the group, patients with Waardenburg syndrome who received cochlear implants were found to have hearing thresholds that allowed access to speech sounds. However, patients who received early intervention and rehabilitation showed better evolution of auditory perception...

Linkage study of DFNB3 responsible for hearing loss in human.

BACKGROUND: Hearing disorders represent a significant health problem worldwide. Recessive inherited cases of the deafness are more prevalent in Pakistan due to consanguineous marriages. Deafness caused by DFNB3 is due to mutation in the gene MYO XVA and its prevalence among Pakistani population is about 5%. MATERIALS AND METHODS: Families with at least two or more individual affected with deafness were selected from different areas of District Okara of Pakistan. Six consanguineous families of different ethnic groups having deaf individuals were studied. All these families had three or more deaf individuals in either two or more sib ships. Family history was taken to minimize the chances of other abnormalities. Pedigrees drawn by using Cyrillic software (version 2.1) showed that all the marriages were consanguineous and the families have recessive mode of inheritance. Three STR markers were selected and amplified on all the samples of six families through PCR. The PCR products were then genotyped on non denaturing polyacrylamide gel electrophoresis (PAGE). Haplotypes were constructed to determine the pattern of inheritance and also to determine whether a family was linked or unlinked with known DFNB3 locus. RESULTS: One out of six families showed linkage to the DFNB3 while rest of the families remained unlinked. Carriers of deafness genes were identified and information was provided to the families on request. CONCLUSION: Knowledge about the genetic causes of deafness provide insight into the variable expression of genes involved in this hereditary problem and may allow the prediction and prevention of associated health problems.

Investigation of the A1555G mutation in mitochondrial DNA (MT-RNR1) in groups of Brazilian individuals with nonsyndromic deafness and normal-hearing.

BACKGROUND: Mutations of mitochondrial DNA were described into two genes: The mitochondrially encoded 12S RNA (MT-RNR1) and the mitochondrially encoded tRNA serineucn (MT-TS1). The A1555G mutation in MT-RNR1 gene is a frequent cause of deafness in different countries. AIM: The aim of this work was to investigate the frequency of the A1555G mutation in the MT-RNR1 gene in the mitochondrial DNA in Brazilians individuals with nonsyndromic deafness, and listeners. MATERIALS AND METHODS: DNA samples were submitted to polymerase chain reaction and to posterior digestion with the Hae III enzyme. RESULTS: Seventy eight (78) DNA samples of deaf individuals were analyzed; 75 showed normality in the region investigated, two samples (2.5%) showed the T1291C substitution, which is not related to the cause of deafness, and one sample (1.3%) showed the A1555G mutation. Among the 70 non-impaired individuals no A1555G mutation or T1291C substitution was found. CONCLUSION: We can affirm that A1555G mutation is not prevalent, or it must be very rare in normal-hearing subjects in the State of Paraná, the south region of Brazil. The A1555G mutation frequency (1.3%) found in individual with nonsyndromic deafness is similar to those found in other populations, with nonsyndromic deafness. Consequently, it should be examined in deafness diagnosis. The investigation of the A1555G mutation can contribute towards the determination of the nonsyndromic deafness etiology, hence, contributing to the correct genetic counseling process.

The study of gene GJB2/DFNB1 causing deafness in humans by linkage analysis from district Peshawar.

Families with at least 2 or more individuals having hereditary hearing loss were enrolled from different areas of Khyber Pakhtoonkhwa, mainly from district Peshawar. Detailed history was taken from each family to minimize the presence of other abnormalities and environmental causes for deafness. Families were questioned about skin pigmentation, hair pigmentation, and problems relating to balance, vision, night blindness, thyroid, kidneys, heart, and infectious diseases like meningitis, antibiotic usage, injury, and typhoid. The pedigree structures were based upon interviews with multiple family members, and pedigrees of the enrolled families were drawn using Cyrillic program (version 2.1). All families showed recessive mode of inheritance. I studied 8 families of these 10. For linkage analyses, studies for DFNB1 locus, 3 STR markers (D13S175, D13S292, and D13S787) were genotyped using polyacrylamide gel electrophoresis (PAGE) and haplotypes were constructed to determined, linkage with DFNB1 locus. From a total of 8 families, a single family-10 showed linkage to DFNB1 locus.

Pesquisa audiológica y molecular para pérdida auditiva por mutación 35delG en el gen de la conexina 26 e infección congénita por citomegalovirus / Audiologic and molecular screening for hearing loss by 35delG mutation in connexin 26 gene and congenital cytomegalovirus infection

Las pérdidas auditivas pueden ser atribuidas a factores genéticos o ambientales. Las mutaciones en el gen de la proteína Cx26 (conexina 26) son responsables de un 30-80% de los casos de pérdida auditiva profunda no sindrómica. La variante 35delG es la prevalente en la población caucásica. Entre los factores ambientales, el citomegalovirus (CMV) es la principal causa de infección congénita. Objetivos. Determinar la prevalencia de infección congénita por CMV y la frecuencia de la mutación 35delG en recién nacidos. Identifcar aquellos con riesgo de pérdida de audición con el fn de realizar un seguimiento audiológico para detectar precozmente las hipoacusias. Material y métodos. Se analizaron 1020 muestras de sangre seca, en papel, de recién nacidos, por PCR convencional y en tiempo real. Se efectuaron las otoemisiones acústicas antes del alta hospitalaria a todos los niños. El seguimiento audiológico se realizó tanto a los portadores de 35delG como a los que tuvieron infección congénita por CMV. Resultados. De los pacientes estudiados, 15 fueron heterocigotas para la mutación 35delG. No se detectaron homocigotas. Seis de las muestras fueron positivas para CMV (resultados confirmados en orina); de ellos, solo un neonato fue sintomático. A todos estos niños se les realizaron las evaluaciones audiológicas; presentaron hipoacusia tres niños con infección congénita por CMV y dos portadores de la mutación 35delG. Conclusión. Se detectó un 1,3% de portadores de la mutación 35delG y una frecuencia de infección congénita por CMV del 0,6%. El seguimiento audiológico de estas dos poblaciones permitió la detección de hipoacusias tardías.

Introduction. Hearing loss may be attributed to genetic and environmental factors. Mutations in the gene of the CX26 protein (connexin 26), are responsible for 30-80% of all cases of non-syndromic profound hearing loss. The 35delG is the most frequent variant in the caucasian population. As to environmental factors, the cytomegalovirus (CMV) is the main cause of congenital infection. Objetives. To determine the prevalence of congenital CMV infection and the frequency of the 35delG mutation in newborns. To identify those at risk of suffering hearing loss in order to do an audiologic follow-up of detected cases. Materials y methods. One thousand and twenty samples of dry blood spots corresponding to newborns were tested using conventional and real time PCR. Audiologic screening was performed to all newborns before hospital discharge. Results. Fifteen out of 1020 subjects were heterozygous for the mutation. No homozygous patients were found. Six out of the samples tested positive for CMV (confrmed by a urine sample), out of which only one newborn was symptomatic. The auditory brainstem response was recorded in all these children. Hearing loss was found in three children with congenital CMV infection and two with 35delG mutation. Conclusion. The frecuency of 35delG mutation carriers in our population was 1.3% and the CMV congenital infection prevalence was 0.6%. Audiologic monitoring of these two populations allowed detection of hearing loss of late onset.

mtDNA mutations, hearing loss and aminoglycoside treatment in Mexicans / Mutações em DNA mitocondrial, hipoacusia e tratamento de mexicanos com aminoglicosídeos

Streptomycin and aminoglycoside derivatives are commonly used to treat tuberculosis and other stubborn infections; these drugs may alter auditory and/or vestibular function. Mutations in mitochondrial DNA have been associated with hypersensitivity to aminoglycosides; no studies have been conducted in Mexicans, which are very prone to such alterations because aminoglycosides have been prescribed carelessly for many years, irrespective of the ailment to be treated. AIM: We investigated "hot spot" mutations described previously as causing inner ear alterations. METHODS: Hot spot mutations at the 12S rRNA gene and the tRNA Serine (UCN) gene were screened by PCR-RFLP and sequencing in 65 subjects undergoing audiological and vestibular testing. STUDY DESIGN: Experimental. RESULTS: 32 individuals had healthy auditory and vestibular function, whereas 33 subjects had auditory affections. We found none of the previously reported mutations related to aminoglycoside hypersensitivity, or non-syndromic hearing loss. Two hearing-impaired patients that had been treated with streptomycin had the T1189C variant of the mitochondrial 12S rRNA region. CONCLUSION: Mutations related to hearing loss in other ethnic backgrounds were not found in Mexicans. However, the T1189C variant is possibly a putative mutation related to aminoglycoside hypersensitivity and was present in 2 patients.

Derivados de aminoglicosídeos e estreptomicina são comumente utilizados para tratar tuberculose e outras infecções mais resistentes; esses medicamentos podem alterar a função vestibular e/ou auditiva. Mutações no DNA mitocondrial têm sido associadas à hipersensibilidade a aminoglicosídeos; não há estudos conduzidos com mexicanos, que são muito predispostos a tais alterações, uma vez que aminoglicosídeos têm sido exageradamente prescritos há anos, sem associações à doença sendo tratada. OBJETIVO: investigamos mutações "hot spot" previamente descritas como causas de alterações no ouvido interno. MÉTODOS: Mutações hot spot no gene 12S rRNA e gene SerinatRNA (UCN) foram triados pela PCR-RFLP e sequenciados em 65 indivíduos sujeitos a exames audiométricos e vestibulares. Desenho do estudo: Experimental. RESULTADOS: 32 indivíduos com funções auditiva e vestibular normais, e 33 indivíduos com doenças auditivas. Não encontramos nenhuma das mutações previamente relatadas como associadas à hipersensibilidade aos aminoglicosídeos, ou perda auditiva não-sindrômica. Dois pacientes com hipoacusia que haviam sido tratados com estreptomicina tinham a variante T1189C na região 12S rRNA. CONCLUSÃO: Mutações associadas à hipoacusia em outras etnias não foram encontradas em mexicanos. Entretanto, a variante T1189C é possivelmente uma mutação associada à hipersensibilidade a aminoglicosídeos, e esteve presente em dois pacientes.