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1.
S. Naz A. Maqsood M. Ramzan A. Fatima M. Iqbal T. Chaudhry M. Lund C.C. Brewer R.J. Morell T.B. Friedman 《Clinical genetics》2017,91(4):589-598
The genetic underpinnings of recessively inherited moderate to severe sensorineural hearing loss are not well understood, despite its higher prevalence in comparison to profound deafness. We recruited 92 consanguineous families segregating stable or progressive, recessively inherited moderate or severe hearing loss. We utilized homozygosity mapping, Sanger sequencing, targeted capture of known deafness genes with massively parallel sequencing and whole exome sequencing to identify the molecular basis of hearing loss in these families. Variants of the known deafness genes were found in 69% of the participating families with the SLC26A4, GJB2, MYO15A, TMC1, TMPRSS3, OTOF, MYO7A and CLDN14 genes together accounting for hearing loss in 54% of the families. We identified 20 reported and 21 novel variants in 21 known deafness genes; 16 of the 20 reported variants, previously associated with stable, profound deafness were associated with moderate to severe or progressive hearing loss in our families. These data point to a prominent role for genetic background, environmental factors or both as modifiers of human hearing loss severity. 相似文献
2.
目的通过分析新生儿听力联合耳聋基因筛查的结果,以及对阳性病例的随访和管理,提高遗传性耳聋的检出率。方法收集33911例新生儿听力联合耳聋基因筛查的结果,应用Sanger测序对听力未通过或基因筛查提示阳性的患儿进行验证。结果听力初筛通过率为93.32%,复筛为87.01%。耳聋基因筛查阳性率为4.18%。GJB2、SLC26A4、GJB3和12SrRNA基因变异的检出率分别为1.98%、1.58%、0.37%和0.25%。共检出126例迟发性耳聋,84例药物性耳聋,4例GJB2纯合/复合杂合变异,5例SLC26A4纯合/复合杂合变异。联合筛查发现GJB2、SLC26A4、GJB3和12SrRNA单杂合变异者听力初筛和复筛未通过的比例分别为6.75%和2.61%、3.3%和1.2%、0.72%和0.14%、0.36%和0%。纯合/单基因复合杂合变异、单基因杂合变异、多基因复合杂合以及GJB3纯合变异组听力筛查未通过率明显高于阴性组,差异具有统计学意义。结论基因检测是对新生儿听力筛查很好的补充。对阳性患儿的追踪管理能够有效提高耳聋的诊断率,但基因筛查不能等同于诊断,应综合分析基因检测、听力筛查和影像学的结果,Sanger/二代测序可作为重要的补充检查手段。 相似文献
3.
Non-syndromic, autosomal-recessive deafness 总被引:5,自引:0,他引:5
Non-syndromic deafness is a paradigm of genetic heterogeneity with 85 loci and 39 nuclear disease genes reported so far. Autosomal-recessive genes are responsible for about 80% of the cases of hereditary non-syndromic deafness of pre-lingual onset with 23 different genes identified to date. In the present article, we review these 23 genes, their function, and their contribution to genetic deafness in different populations. The wide range of functions of these DFNB genes reflects the heterogeneity of the genes involved in hearing and hearing loss. Several of these genes are involved in both recessive and dominant deafness, or in both non-syndromic and syndromic deafness. Mutations in the GJB2 gene encoding connexin 26 are responsible for as much as 50% of pre-lingual, recessive deafness. By contrast, mutations in most of the other DFNB genes have so far been detected in only a small number of families, and their contribution to deafness on a population scale might therefore be limited. Identification of all genes involved in hereditary hearing loss will help in our understanding of the basic mechanisms underlying normal hearing, in early diagnosis and therapy. 相似文献
4.
Petersen MB 《Clinical genetics》2002,62(1):1-13
Non-syndromic deafness is a paradigm of genetic heterogeneity. More than 70 loci have been mapped, and 25 of the nuclear genes responsible for non-syndromic deafness have been identified. Autosomal-dominant genes are responsible for about 20% of the cases of hereditary non-syndromic deafness, with 16 different genes identified to date. In the present article we review these 16 genes, their function and their contribution to deafness in different populations. The complexity is underlined by the fact that several of the genes are involved in both dominant and recessive non-syndromic deafness or in both non-syndromic and syndromic deafness. Mutations in eight of the genes have so far been detected in only single dominant deafness families, and their contribution to deafness on a population base might therefore be limited, or is currently unknown. Identification of all genes involved in hereditary hearing loss will help in the understanding of the basic mechanisms underlying normal hearing, will facilitate early diagnosis and intervention and might offer opportunities for rational therapy. 相似文献
5.
Mutations in the DFNB1 locus, where two connexin genes are located (GJB2 and GJB6), account for half of congenital cases of nonsyndromic autosomal recessive deafness. Because of the high frequency of DFNB1 gene mutations and the availability of genetic diagnostic tests involving these genes, they are the best candidates to develop a risk prediction model of being hearing impaired. People undergoing genetic counseling are normally interested in knowing the probability of having a hearing impaired child given his/her family history. To address this, a Mendelian model that predicts the probability of being a carrier of DFNB1 mutations, using family history of deafness, has been developed. This probability will be useful as additional information to decide whether or not a genetic test should be performed. This model incorporates Mendelian mode of inheritance, the age of onset of the disease, and the current age of hearing family members. The carrier probabilities are obtained using Bayes' theorem, in which mutation prevalence is used as the prior distribution. We have validated our model by using information from 305 families affected with congenital or progressive nonsyndromic deafness, in which genetic analysis of GJB2 and GJB6 had already been performed. This model works well, especially in homozygous carriers, showing a high discriminative power. This indicates that our proposed model can be useful in the context of clinical counseling of autosomal recessive disorders. 相似文献
6.
Adebolajo Adeyemo Rabia Faridi Parna Chattaraj Rizwan Yousaf Risa Tona Samuel Okorie Thashi Bharadwaj Liz M. Nouel-Saied Anushree Acharya Isabelle Schrauwen Robert J. Morell Suzanne M. Leal Thomas B. Friedman Andrew J. Griffith Isabelle Roux 《European journal of human genetics : EJHG》2022,30(1):42
Although variant alleles of hundreds of genes are associated with sensorineural deafness in children, the genes and alleles involved remain largely unknown in the Sub-Saharan regions of Africa. We ascertained 56 small families mainly of Yoruba ethno-lingual ancestry in or near Ibadan, Nigeria, that had at least one individual with nonsyndromic, severe-to-profound, prelingual-onset, bilateral hearing loss not attributed to nongenetic factors. We performed a combination of exome and Sanger sequencing analyses to evaluate both nuclear and mitochondrial genomes. No biallelic pathogenic variants were identified in GJB2, a common cause of deafness in many populations. Potential causative variants were identified in genes associated with nonsyndromic hearing loss (CIB2, COL11A1, ILDR1, MYO15A, TMPRSS3, and WFS1), nonsyndromic hearing loss or Usher syndrome (CDH23, MYO7A, PCDH15, and USH2A), and other syndromic forms of hearing loss (CHD7, OPA1, and SPTLC1). Several rare mitochondrial variants, including m.1555A>G, were detected in the gene MT-RNR1 but not in control Yoruba samples. Overall, 20 (33%) of 60 independent cases of hearing loss in this cohort of families were associated with likely causal variants in genes reported to underlie deafness in other populations. None of these likely causal variants were present in more than one family, most were detected as compound heterozygotes, and 77% had not been previously associated with hearing loss. These results indicate an unusually high level of genetic heterogeneity of hearing loss in Ibadan, Nigeria and point to challenges for molecular genetic screening, counseling, and early intervention in this population.Subject terms: Genetics research, Medical genomics 相似文献
7.
8.
Zippora Brownstein Suleyman Gulsuner Tom Walsh Fábio T.A. Martins Shahar Taiber Ofer Isakov Ming K. Lee Mor Bordeynik-Cohen Maria Birkan Weise Chang Silvia Casadei Nada Danial-Farran Amal Abu-Rayyan Ryan Carlson Lara Kamal Asgeir Ö. Arnthórsson Meirav Sokolov Dror Gilony Noga Lipschitz Moshe Frydman Bella Davidov Michal Macarov Michal Sagi Chana Vinkler Hana Poran Reuven Sharony Nadra Samra Na'ama Zvi Hagit Baris-Feldman Amihood Singer Ophir Handzel Ronna Hertzano Doaa Ali-Naffaa Noa Ruhrman-Shahar Ory Madgar Efrat Sofrin-Drucker Amir Peleg Morad Khayat Mordechai Shohat Lina Basel-Salmon Elon Pras Dorit Lev Michael Wolf Eirikur Steingrimsson Noam Shomron Matthew W. Kelley Moien N. Kanaan Stavit Allon-Shalev Mary-Claire King Karen B. Avraham 《Clinical genetics》2020,98(4):353-364
9.
Elodie M. Richard Regie Lyn P. Santos‐Cortez Rabia Faridi Atteeq U. Rehman Kwanghyuk Lee Mohsin Shahzad Anushree Acharya Asma A. Khan Ayesha Imtiaz Imen Chakchouk Christina Takla Izoduwa Abbe Maria Rafeeq Khurram Liaqat Taimur Chaudhry Michael J. Bamshad Deborah A. Nickerson Isabelle Schrauwen Shaheen N. Khan Robert J. Morell Saba Zafar Muhammad Ansar Zubair M. Ahmed Wasim Ahmad Sheikh Riazuddin Thomas B. Friedman Suzanne M. Leal Saima Riazuddin 《Human mutation》2019,40(1):53-72
Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome‐wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 70 (42.9%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL‐associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling, and guide application of future gene‐based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders. 相似文献
10.
《European journal of medical genetics》2023,66(1):104658
Hearing Loss (HL) is one of the most prevalent congenital diseases in humans and is etiologically highly heterogeneous. To date, over 360 genes have been identified that are involved in mouse or human deafness. SPNS2 is one of these genes that has been attributed to deafness in recent years. In this study, we identified two novel damaging variants of c.906G>A; p.(Trp302*) and c.487G>A; p.(Asp163Asn) in the SPNS2 gene in an eight-year-old female with bilateral sensorineural hearing loss who also presents with congenital hypothyroidism and coronary heart disease. Sanger sequencing confirmed that the variants are compound heterozygote. In addition, in silico analysis by various tools predicted that these variants are damaging. To date, these detected variants have not been reported in any of the existing public databases. We hope that identification of more variants in SPNS2 provide new insights into its role in deafness. 相似文献
11.
Assessment of the genetic causes of recessive childhood non-syndromic deafness in the UK - implications for genetic testing 总被引:1,自引:0,他引:1
Hutchin T Coy NN Conlon H Telford E Bromelow K Blaydon D Taylor G Coghill E Brown S Trembath R Liu XZ Bitner-Glindzicz M Mueller R 《Clinical genetics》2005,68(6):506-512
Approximately one in 2000 children is born with a genetic hearing impairment, mostly inherited as a non-syndromic, autosomal recessive trait, for which more than 30 different genes have been identified. Previous studies have shown that one of these genes, connexin 26 (GJB2), accounts for 30-60% of such deafness, but the relative contribution of the many other genes is not known, especially in the outbred UK population. This lack of knowledge hampers the development of diagnostic genetic services for deafness. In an effort to determine the molecular aetiology of deafness in the population, 142 sib pairs with early-onset, non-syndromic hearing impairment were recruited. Those in whom deafness could not be attributed to GJB2 mutations were investigated further for other mapped genes. The genetic basis of 55 cases (38.7%) was established, 33.1% being due to mutations in the GJB2 gene and 3.5% due to mutations in SLC26A4. None of the remaining 26 loci investigated made a significant contribution to deafness in a Caucasian population. We suggest that screening the GJB2 and SLC26A4 genes should form the basis of any genetic testing programme for childhood deafness and highlight a number of important issues for consideration and future work. 相似文献
12.
Songfeng Zou Xueshuang Mei Weiqiang Yang Rvfei Zhu Tao Yang Hongyi Hu 《Clinical genetics》2020,97(2):352-356
Genetic causes of hearing loss are highly heterogeneous and often ethnically specific. In recent years, a variety of next-generation sequencing (NGS) panels have been developed to target deafness-causative genes. Whole-exome sequencing (WES), on the other hand, was rarely used for genetic testing for deafness. In this study, we performed WES in 38 sporadic Chinese Han deaf patients who have been pre-excluded for mutations in common deafness genes GJB2, SLC26A4 and MT-RNR1. Non-synonymous variants have been filtered based on their minor allele frequencies in public databases and ethnically matched controls. Bi-allelic pathogenic mutations in eight deafness genes, OTOF, TRIOBP, ESPN, HARS2, CDH23, MYO7A, USH1C and TJP2, were identified in 10 patients, with 17 mutations identified in this study not being associated with deafness previously. For the rest 28 patients, possibly bi-allelic rare non-synonymous variants in an averaged 4.7 genes per patient were identified as candidate pathogenic causes for future analysis. Our study showed that WES may provide a unified platform for genetic testing of deafness and enables retro-analyzing when new causative genes are revealed. 相似文献
13.
近 20年来,遗传性疾病的基因治疗研究日益深入。作为临床试验中相对较为安全的基因治疗载体,重组腺相关病毒AAV在遗传性疾病的基础和临床研究中被广泛使用。遗传性耳聋 (包括非综合征和综合征耳聋) 的主要致病原因是遗传物质,即基因发生异常突变。自1997年发现首个耳聋基因以来,目前已鉴定123个非综合征耳聋基因,超过40个综合征耳聋基因。遗传性耳聋的临床发病率高,但缺乏有效的治疗方法。随着分子生物学和基因治疗临床研究的发展,重组 AAV介导的基因治疗开始广泛应用于耳聋治疗的基础研究之中。本文对重组AAV及其介导的遗传性疾病,尤其是遗传性耳聋相关的基因治疗的概念、策略及其应用作一综述。 相似文献
14.
de Oliveira CA Alexandrino F Christiani TV Steiner CE Cunha JL Guerra AT Sartorato EL 《American journal of medical genetics. Part A》2007,(14):1574-1579
Hereditary hearing loss is a complex disorder that involves a large number of genes. In developed countries, 1 in 1,000 children is born with deafness severe enough to require special education services, and about 60% of the cases of isolated deafness have a genetic origin. Although more than 100 genes for hearing loss are known currently, only a few are routinely tested in the clinical practice. In this study, we present our findings from the molecular diagnostic screening of the GJB2 and GJB3 genes, del(GJB6-D13S1,830) and del(GJB6-D13S1,854) deletions in the GJB6 gene, Q829X mutation in the otoferlin gene (OTOF) and, the A1,555G and A7,445G mutations in the mitochondrial genome over an 8-year period. Mutations analysis in the previously mentioned genes and mutations was performed on 645 unrelated Brazilian patients with hearing loss who fell into two different testing groups. Different mutations in the GJB2 gene were responsible for most of cases studied, but deletions in the GJB6 gene as well as mitochondrial mutations were also found. While most cases of hearing loss in this country are due to environmental factors, the genetic etiology of deafness will increasingly be determined as more genetic tests become available. 相似文献
15.
目的 探讨听力筛查联合遗传性耳聋基因检测在新生儿筛查中的应用。方法 选取2018年12月~2019年7月我院接受产检的产妇509例,对所有产妇进行遗传性耳聋基因检测,并在产妇完成分娩后48 h对新生儿作常规听力筛查,确诊新生儿是否存在听力障碍。结果 509例产妇经遗传性耳聋基因检测显示阳性16例,阳性率3.14%;听力筛查不通过同时伴有耳聋基因突变新生儿共5例,听力学诊断结合随访确诊3例新生儿存在听力障碍,包含1例GJB2 299-300delAT突变,1例GJB2 235delC突变、1例SLC26A4 919-2A>G突变。结论 在新生儿常规听力筛查的同时提供遗传性耳聋基因检测,能够有效弥补听力筛查的不足,可用作听力筛查工作的有效补充,有助于筛查出迟发型及潜在性耳聋患儿,提升听力障碍的检出率。 相似文献
16.
Taneja PR Pandya A Foley DL Nicely LV Arnos KS 《American journal of medical genetics. Part A》2004,(1):17-21
Recent advances have made molecular genetic testing for several forms of deafness more widely available. Previous studies have examined the attitudes of the deaf towards genetic testing, including prenatal diagnosis. This study examines the attitudes of deaf college students towards universal newborn hearing screening, including molecular testing for specific forms of deafness, as well as the utilization of genetic test results for mate selection. We found that there may be differences in the attitudes of deaf individuals who associate closely with the deaf community (DC), and those who have equal involvement with both the deaf and hearing communities (EIC). The majority perceived newborn hearing screening for deafness to be helpful. However, more members of the EIC than the DC groups support newborn testing for genes for deafness. While there was reported interest in using genetic testing for partner selection, most participants reported they would not be interested in selecting a partner to have children with a specific hearing status. The results of this study point out important differences that genetic professionals should be aware of when counseling deaf individuals. 相似文献
17.
Tlili A Charfedine I Lahmar I Benzina Z Mohamed BA Weil D Idriss N Drira M Masmoudi S Ayadi H 《Human mutation》2005,25(5):503
Approximately 80% of hereditary hearing loss is non-syndromic. Non-syndromic deafness is the most genetically heterogeneous trait. The most common and severe form of hereditary hearing impairment is autosomal recessive non-syndromic hearing loss (ARNSHL), accounting for approximately 80% of cases of genetic deafness. To date, 22 genes implicated in ARNSHL have been identified. Recently a gene, DFNB31/WHRN, which encodes a putative PDZ scaffold protein called whirlin, was found to be responsible for the ARNSHL DFNB31. We found evidence for linkage to the DFNB31locus in a consanguineous Tunisian family segregating congenital profound ARNSHL. Mutation screening of DFNB31/WHRNrevealed four nonpathogenic sequence variants and a novel frameshift mutation [c.2423delG] + [c.2423delG] that changed the reading frame and induced a novel stop codon at amino acid 818 ([p.Gly808AspfsX11] + [p.Gly808AspfsX11]). To determine the contribution of the DFNB31locus in the childhood deafness, we performed linkage analysis in 62 unrelated informative families affected with ARNSHL. No linkage was found to this locus. From this study, we concluded that DFNB31/WHRN is most likely to be a rare cause of ARNSHL in the Tunisian population. 相似文献
18.
Kevin T. Booth Hela Azaiez Kimia Kahrizi Donghong Wang Yuzhou Zhang Kathy Frees Carla Nishimura Hossein Najmabadi Richard J Smith 《Human mutation》2018,39(3):433-440
Dysregulation of splicing is a common factor underlying many inherited diseases including deafness. For one deafness‐associated gene, DFNA5, perturbation of exon 8 splicing results in a constitutively active truncated protein. To date, only intronic mutations have been reported to cause exon 8 skipping in patients with DFNA5‐related deafness. In five families with postlingual progressive autosomal dominant non‐syndromic hearing loss, we employed two next‐generation sequencing platforms—OtoSCOPE and whole exome sequencing—followed by variant filtering and prioritization based on both minor allele frequency and functional consequence using a customized bioinformatics pipeline to identify three novel and two recurrent mutations in DFNA5 that segregated with hearing loss in these families. The three novel mutations are all missense variants within exon 8 that are predicted computationally to decrease splicing efficiency or abolish it completely. We confirmed their functional impact in vitro using mini‐genes carrying each mutant DFNA5 exon 8. In so doing, we present the first exonic mutations in DFNA5 to cause deafness, expand the mutational spectrum of DFNA5‐related hearing loss, and highlight the importance of assessing the effect of coding variants on splicing. 相似文献
19.
Shin-ichi Usami Shin-ya Nishio Hideaki Moteki Maiko Miyagawa Hidekane Yoshimura 《Anatomical record (Hoboken, N.J. : 2007)》2020,303(3):563-593
While cochlear implantation (CI) technology has greatly improved over the past 40 years, one aspect of CI that continues to pose difficulties is the variability of outcomes due to numerous factors involved in postimplantation performance. The electric acoustic stimulation (EAS) system has expanded indications for CI to include patients with residual hearing, and is currently becoming a standard therapy for these patients. Genetic disorders are known to be the most common cause of congenital/early-onset sensorineural hearing loss, and are also involved in a considerable proportion of cases of late-onset hearing loss. There has been a great deal of progress in the identification of deafness genes over the last two decades. Currently, more than 100 genes have been reported to be associated with non-syndromic hearing loss. Patients possessing a variety of deafness gene mutations have achieved satisfactory auditory performance after CI/EAS, suggesting that identification of the genetic background facilitates prediction of post-CI/EAS performance. When the intra-cochlear etiology is associated with a specific genetic background, there is a potential for good CI performance. Thus, it is essential to determine which region of the cochlea is affected by identifying the responsible genes. This review summarizes the genetic background of the patients receiving CI/EAS, and introduces detailed clinical data and CI/EAS outcomes in representative examples. Anat Rec, 303:563–593, 2020. © 2020 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists. 相似文献
20.
Zippora Brownstein Amal Abu-Rayyan Daphne Karfunkel-Doron Serena Sirigu Bella Davidov Mordechai Shohat Moshe Frydman Anne Houdusse Moien Kanaan Karen B Avraham 《European journal of human genetics : EJHG》2014,22(6):768-775
Hereditary hearing loss is genetically heterogeneous, with a large number of genes and mutations contributing to this sensory, often monogenic, disease. This number, as well as large size, precludes comprehensive genetic diagnosis of all known deafness genes. A combination of targeted genomic capture and massively parallel sequencing (MPS), also referred to as next-generation sequencing, was applied to determine the deafness-causing genes in hearing-impaired individuals from Israeli Jewish and Palestinian Arab families. Among the mutations detected, we identified nine novel mutations in the genes encoding myosin VI, myosin VIIA and myosin XVA, doubling the number of myosin mutations in the Middle East. Myosin VI mutations were identified in this population for the first time. Modeling of the mutations provided predicted mechanisms for the damage they inflict in the molecular motors, leading to impaired function and thus deafness. The myosin mutations span all regions of these molecular motors, leading to a wide range of hearing phenotypes, reinforcing the key role of this family of proteins in auditory function. This study demonstrates that multiple mutations responsible for hearing loss can be identified in a relatively straightforward manner by targeted-gene MPS technology and concludes that this is the optimal genetic diagnostic approach for identification of mutations responsible for hearing loss. 相似文献