基于西北少数民族的聋病资源库构建及基因诊断策略研究
|
摘要
听力损失影响人的言语功能进而导致社会交流障碍,因其发病率高而成为医学界研究的热点。从1995年克隆第一个耳聋基因起,超过80个非综合征耳聋相关基因被发现,越来越多的聋病分子病因得以揭示。中国人口的多民族结构蕴含着丰富的遗传资源,特别是不同族源的少数民族人群更为珍贵。本研究旨在进行中国西北地区少数民族耳聋资源的收集,建立一个覆盖西北地区的包含主要少数民族的临床资源和遗传资源库。在此基础上,通过开展三种常见的耳聋相关基因的分子流行病学研究,并对一个耳聋家系进行候选基因突变研究,试图揭示这些基因在少数民族耳聋人群的流行状况,绘制各民族的聋病基因突变频谱,分析开展耳聋家系致病基因定位克隆的有效方法,探索针对少数民族的基因诊断策略。我们研究的主要内容由以下四部分组成：第一章：中国西北地区少数民族聋病资源库建设
少数民族耳聋群体较为稀缺,遗传性耳聋资源有减少的趋势。为了保护少数民族的遗传性耳聋资源,我们研究建立西北地区少数民族的聋病资源库。研究中制定了资源库建设的规范流程,通过本地区各特教学校、各级残联及医院门诊等渠道收集耳聋散发病例及耳聋家系资源,进行问卷调查、物理检查、听力学检查并绘制家系图谱,签订知情同意书并抽取外周静脉血,提取基因组DNA,建立全套资料的数据化管理模式。我们共收集到少数民族1673例耳聋散发病例和146个遗传性耳聋家系,完成了临床和遗传资源的收集,为进一步开展遗传学研究积累了资源。我们认为需要进一步加强少数民族耳聋资源的保护,建立科学完善的资源库管理体系。第二章：西北少数民族非综合征感音神经性聋的GJB2基因突变筛查研究
GJB2基因是目前发现的先天性耳聋最常见的分子病因,GJB2基因编码缝隙连接蛋白Cx26,在内耳电解质交换和细胞间信息传递发挥重要作用,与人类听觉功能关系密切。我们在西北少数民族散发感音神经性聋患者群体中开展GJB2基因的突变研究,目的是分析该基因的流行状况,揭示少数民族的热点突变,探讨适合这些耳聋人群的基因诊断策略。研究中完成了共1330例非综合征感音神经性听力损失患者的GJB2基因的突变筛查,并且完成了同地区457例汉族耳聋患者的比较研究。结果在少数民族发现了11种突变形式,包括一种新的突变：c.257C>G。少数民族共有202例患者发现突变或序列改变,纯合突变75例,杂合突变92例,复合杂合突变35例。这些基因型的突变频率为15.19%(202/1330),同地区汉族人群的突变频率为19.04%(87/457)。少数民族群体与汉族的突变频率之间没有显著性差异,比较各民族与汉族的GJB2基因突变频率差异,其中维吾尔族与汉族存在统计学差异,其他各民族之间无统计学差异。各民族GJB2基因突变基因型以框移突变为主,这类基因型决定了耳聋表型是以重度及极重度聋为多见。在少数民族人群中等位基因频率最高的四种突变是c.235delC、c.35delG、 c.109G>A和c.299-300delAT,藏族的热点突变是c.235delC和c.109G>A,东乡族的热点突变分别是c.299-300delAT和c.235delC,回族是c.235delC和c.109G>A,哈萨克族是c.35delG,维吾尔族是c.235delC、c.35delG,汉族人群的热点突变是c.235delC、c.109G>A和c.299-300delAT,各民族的GJB2基因突变频率与其种族背景相一致,其中哈萨克族和维吾尔族具有明显的高加索背景表现。研究中我们绘制了各民族完整的GJB2基因突变频谱,可以为针对各民族的个性化的基因诊断和大面积筛查提供方法学依据。另外考虑到基因的结构特点和突变位点的分散性,GJB2基因诊断模式以全编码序列的筛查为宜。第三章：SLC26A4基因及IntDNA1555A>G突变在西北少数民族非综合征感音神经性听力损失患者的筛查研究
前庭水管扩大是先天性耳聋最常见的内耳畸形,与这一疾病相关的SLC26A4基因与耳聋关系密切。线粒体DNAA1555G突变与氨基糖苷类抗生素导致耳聋有相关性,该突变检测有利于揭示药物性聋和环境因素的关系。我们对西北地区少数民族共1330例非综合征感音神经性聋患者,以PCR及直接测序检测SLC26A4基因第8、第19外显子的突变,运用PCR-RFLP筛查1ntDNA1555A>G点突变。在共1330例少数民族患者中,筛查出SLC26A4基因c.919-2A>G、c.2168A>G、c.2162C>T三种突变形式,检测到七种基因型,包括纯合26例,杂合40例,复合杂合突变5例,其中双等位基因的突变频率为2.33%。同期进行的本地区汉族457例聋人检测到6种基因型,包括纯合15例,杂合31例及复合杂合突变8例,双等位基因突变频率为5.03%。分析显示汉族同藏族、东乡族及维族的该基因突变频率有统计学差异,回族与东乡族和维族均有差异。研究证实c.919-2A>G突变是汉族聋人的热点突变,这一突变在汉族与藏族、东乡族及维吾尔族均存在统计学差异,维族与回族及哈萨克族有差异,回族与东乡族存在差异。研究中检测出mtDNA1555A>G突变的患者有28例,突变频率为2.11%,同地区457例汉族患者中突变者有32例,突变频率为7.00%,两者之间有显著性差异。在106例AAID患者中有9例检测到mtDNA1555A>G突变,AAID患者中突变频率为8.49%。各少数民族耳聋患者频率比较显示汉族与回族、东乡族及维吾尔族之间的突变频率存在统计学差异。研究证实SLC26A4基因在各少数民族与汉族的突变频谱不同,热点突变各异,因此需要针对各少数民族研究其突变频谱,制定适合各民族的基因诊断策略和产前诊断方法。研究表明有必要在本地区少数民族耳聋人群中开展mtDNA1555A>G突变的基因诊断,在散发耳聋患者、遗传性耳聋家系开展该突变检测,进行科学干预有助于延缓和减少药物性耳聋的发生。
第四章常染色体显性遗传非综合征耳聋家系的候选基因分析
遗传性疾病的基因定位克隆方法多样,需要根据遗传资源的特征选择合适的研究方法。本文旨在探索适宜于遗传性耳聋病因学研究的有效方法。针对一个遗传性耳聋大家系,我们系统进行临床资料和表型特点研究,并通过候选基因突变筛查方法,明确了该家系的致病基因。首先通过对家系中耳聋患者发病特点的分析,我们明确其遗传方式为常染色体显性遗传。总结本家系表型特点有：耳聋首先以高频听力损失为主,后期影响到全频听力,部分患者表现有前庭功能障碍的症状。通过对表型的详尽分析,研究中将候选基因局限在少数几个基因,进而对最符合表型特点的COCH基因全部外显子进行突变筛查,发现了该基因第8外显子c.485G>A突变为致病突变,该突变与家系中遗传性状共分离。研究中发现该家系中听力损失外显率为100%,听力损失随年龄增长而逐渐加重,前庭功能障碍的外显率为22.22%,前庭障碍症状与听力损失的程度没有相关性。从听力学特点和前庭功能障碍特征判断,该家系与梅尼埃病的临床表现不符。我们认为遗传性耳聋家系的基因定位克隆,首选位置克隆和候选基因克隆法,通过连锁分析能够定位耳聋相关基因的位置,候选基因克隆法具有经济快捷的优势。收集详实的临床资料和听力学资料、充分分析家系临床特征对于选择适宜的研究方法是十分必要的。
Hearing loss seriously affects the patients'function of audition and speech, which leads to the barriers of social communication. The high morbidity makes it a research hot issue in medical field. Since the first deafness gene was cloned in1995, more than40NSHL related genes have been found and molecular mechanism of deafness has been revealed. China is a big family, which contains56ethnic groups and has rich genetic resources especially from ancient minority ethnic groups. Therefore, it is necessary to carry out the research of deafness genes of ethnic minorities in China. This study aims to collect the deafness resources from ethnic minorities in the northwest China, and build a clinical and genetic resource library to cover major ethnic minorities in the northwest. Based on this, three types of high-risk deafness genes'molecular epidemiology research are carried out to reveal the relations of these genes and deafness,to explore the strategies for developing the deafness gene diagnosis and to find the ways to prevent deafness through human intervention. The main content of the research is comprised of four parts:
The first chapter:The construction of deaf resources library from ethnic minorities in northwest China.
The genetic resourceof Northwest minority deaf population is extremely scarce, and has a decreasing trend. We first design the standard process of the construction of the resources library. Then we collect deafness sporadic cases and deaf family resources, conduct questionnaire surveys, physical examination, audiological examination and family mapping, sign informed consent form and extract the peripheral venous blood, extract genomic DNA to establish a full set of libraty for digital management. We have collected1673deafness sporadic cases and146hereditary deafness families from ethnic minorities. It has accumulated resources for further genetic studies.We believe that protection of minority ethnic group deafness resources needs to be further strengthened, and a scientific and perfect resource libraty management system needs to be established.
The second chapter:Deafness related gene GJB2screening and diagnosis strategy research in the northwest ethnic minorities.
GJB2gene is the most common molecular etiology in congenital deafness. GJB2gene codes gap junction protein Cx26, which plays an important role in the inner ear electrolyte exchange and information transmission between cells, and is closely associated with human auditory function.We carry out GJB2gene's screening study in northwest minority deafness patients to analyze the epidemic condition of the gene, reveal the mutation hotspot of ethnic minorities and explore the genetic diagnosis strategy suitable for the deaf people.In this study, we finished1330ethnic minorities NSHL cases and457Han ethnic NSHL cases for GJB2gene mutation screening. The results showed that11mutation forms were found, including a new mutation:c.275C>G.202mutation or sequence change cases,75cases of homozygous mutations,92cases of heterozygous mutations and35cases of compound heterozygous mutations were found in ethnic minorities.The mutation frequency was15.19%(202/1330) in ethnic minorities and19.04%(87/457) in ethnic Han. It has no significant difference in allele frequency from ethnic minorities and ethnic Han. No differences were found between the ethnic groups except Uygur and Han.Frameshift mutation is the main form of GJB2gene in various ethnic groups. This gene type has determined that the hearing loss is either serious or profound.In ethnic minorities, c.235delC, c.35delG, c.109G>A and c.299-300delAT were the highest allele frequency forms. Different nations have different hotspots: Tibetan was c.235delC and c.109G>A; Dongxiang was c.299-300delAT and c.235delC; Hui ethnic was c.235delC and c.109G>A; Kazak was c.35delG; Uygur was c.235delC and c.35delG; Han ethnic was c.235delC, c.109G>A and c.299-300delAT.The research also showed that mutation frequency of each ethnic group was consistent with its ethnic background, especially in kazak and uighurs which has obvious Caucasus background.In this study, complete GJB2gene mutation spectrums of all ethnic groups were made, which could provide the methodology basis for personalized genetic diagnosis and widespread gene screening in all ethnic groups. Considering the structural characteristics and the dispersion of mutations, it is advisable to choose the diagnosis model of the whole coding sequence screening.
The third chapter:SLC26A4geneand mtDNAA1555G mutation screeningof non-syndrome sensorineural deafness in the northwest ethnic minorities.
Vestibular aqueduct expandingis the most common inner ear malformation.,SLC26A4gene which associated with vestibular aqueduct expanding is closely associated with deafness. mtDNAA1555G mutation associates with deafness caused by AmAn. The mutation detection is helpful to explore the relationship between drug deafness and environmental factors. In this study, we collected1330patients with NSHL from ethnic minorities in northwest China to carry out SLC26A4gene (8and9exons) and mtDNAA1555G mutation screening through PCR-RFLP or direct sequencing methods.In SLC26A4gene, three mutation forms have been found:919-2A>G, c.2168A>G and2162C>T. Seven genetypes were found in ethnic minorities, including26cases of homozygous,40cases of hybrid and5cases of compound heterozygous; six genetypes were found in ethnic Han, including15cases of homozygous,31cases of hybrid and8cases of compound heterozygous. The detection rates of homozygous and compound heterozygous mutations were2.33%(31/1330) and5.03%(23/457), respectively. The comparison of different ethnics showed that statistically significant differences had been found between ethnic Han and Tibetan, Dongxiang, Uighur. The difference also existed in ethnic Hui and Dongxiang and Uighur. The study also confirmed that919-2A>G allele frequencies had statistically significant differences between ethnic Han and Tibetan, Dongxiang, Uyghur; between Uighur and ethnic Hui, Kazak; and also between ethnic Hui and Dongxiang. In the study of mtDNA, we found that:28cases had mtDNAA1555G mutation in ethnic minorities, mutation frequency was2.11%(28/1330);32cases had mtDNAA1555G mutation in ethnic Han, mutation frequency was7.00%(32/457). Statistical processing showed that there was a significant difference between mutation frequency of ethnic minorities and ethnic Han.In106cases of AAID,9cases had mtDNAA1555G mutation and mutation frequency was8.49%.After statistical analysis, there is a statistically significant difference on mtDNAA1555G mutation frequency between Dongxiang and ethnic Han, and also between ethnic Hui and Uighur.The results showed that all the ethnic minorities have the unique spectrum of SLC26A4gene mutation, and the hotspots are not identical. We need to formulate genetic diagnosis strategy and choose the suitable methods of gene diagnosis and prenatal diagnosis for different ethnics; it is necessary to carry out the mtDNA1555A>G mutation genetic diagnosis in the region deafness people from ethnic minorities, which will help to slow down and reduce the occurrence of AAID.
The fourth chapter:Analysis of candidate genes in an Autosomal dominant non-syndrome hearing loss pedigree
There are many gene positional cloning methods for genetic disease. It is necessary to choose the appropriate research method according to the characteristics of the genetic resources. In this study, the purpose was to explore suitable and effective approach to the study of the hereditary deafness etiology.We carried out systematic research in clinical data and phenotypic characteristics of a hereditary deafness pedigree. Through candidate gene mutation screening, we made clear the pathogenic genes. Firstly, we defined the genetic way as autosomal dominant inheritance through the analysis of the onset of the characteristics of deafness patients. The phenotypic characteristics are summarized as:High frequency hearing loss was the first performance, and then the whole frequency hearing would be affected. Some patients had symptoms of vestibular function obstacle performance. Through the detailed analysis of the phenotype, candidate genes were confined to a handful of genes. And then we chose COCH gene which accord the most with the characteristics of phenotype to screen mutations in all exons. c.485G>A was found in exon8and mutated into pathogenic mutation. The mutation and deafness phenotype was in the line of separation.The study found that:the hearing loss penetrance was100%, which gradually aggravated with age; penetrance of vestibular dysfunction was22.22%, which was not associated with the degree of hearing loss. Judging from characteristics of audiological and vestibular function obstacle features, the family was not conforming to the clinical manifestations of Meniere's disease. We believe that the hereditary deafness family gene mapping, preferred position cloning and candidate gene cloning methods can locate the position of deafness genes through linkage analysis.Candidate gene cloning methodis economical, fast and convenient. Collecting detailed clinical data and audiology data, analyzing fully of clinical characteristics are indispensable for choosing appropriate research method.
少数民族耳聋群体较为稀缺,遗传性耳聋资源有减少的趋势。为了保护少数民族的遗传性耳聋资源,我们研究建立西北地区少数民族的聋病资源库。研究中制定了资源库建设的规范流程,通过本地区各特教学校、各级残联及医院门诊等渠道收集耳聋散发病例及耳聋家系资源,进行问卷调查、物理检查、听力学检查并绘制家系图谱,签订知情同意书并抽取外周静脉血,提取基因组DNA,建立全套资料的数据化管理模式。我们共收集到少数民族1673例耳聋散发病例和146个遗传性耳聋家系,完成了临床和遗传资源的收集,为进一步开展遗传学研究积累了资源。我们认为需要进一步加强少数民族耳聋资源的保护,建立科学完善的资源库管理体系。第二章：西北少数民族非综合征感音神经性聋的GJB2基因突变筛查研究
GJB2基因是目前发现的先天性耳聋最常见的分子病因,GJB2基因编码缝隙连接蛋白Cx26,在内耳电解质交换和细胞间信息传递发挥重要作用,与人类听觉功能关系密切。我们在西北少数民族散发感音神经性聋患者群体中开展GJB2基因的突变研究,目的是分析该基因的流行状况,揭示少数民族的热点突变,探讨适合这些耳聋人群的基因诊断策略。研究中完成了共1330例非综合征感音神经性听力损失患者的GJB2基因的突变筛查,并且完成了同地区457例汉族耳聋患者的比较研究。结果在少数民族发现了11种突变形式,包括一种新的突变：c.257C>G。少数民族共有202例患者发现突变或序列改变,纯合突变75例,杂合突变92例,复合杂合突变35例。这些基因型的突变频率为15.19%(202/1330),同地区汉族人群的突变频率为19.04%(87/457)。少数民族群体与汉族的突变频率之间没有显著性差异,比较各民族与汉族的GJB2基因突变频率差异,其中维吾尔族与汉族存在统计学差异,其他各民族之间无统计学差异。各民族GJB2基因突变基因型以框移突变为主,这类基因型决定了耳聋表型是以重度及极重度聋为多见。在少数民族人群中等位基因频率最高的四种突变是c.235delC、c.35delG、 c.109G>A和c.299-300delAT,藏族的热点突变是c.235delC和c.109G>A,东乡族的热点突变分别是c.299-300delAT和c.235delC,回族是c.235delC和c.109G>A,哈萨克族是c.35delG,维吾尔族是c.235delC、c.35delG,汉族人群的热点突变是c.235delC、c.109G>A和c.299-300delAT,各民族的GJB2基因突变频率与其种族背景相一致,其中哈萨克族和维吾尔族具有明显的高加索背景表现。研究中我们绘制了各民族完整的GJB2基因突变频谱,可以为针对各民族的个性化的基因诊断和大面积筛查提供方法学依据。另外考虑到基因的结构特点和突变位点的分散性,GJB2基因诊断模式以全编码序列的筛查为宜。第三章：SLC26A4基因及IntDNA1555A>G突变在西北少数民族非综合征感音神经性听力损失患者的筛查研究
前庭水管扩大是先天性耳聋最常见的内耳畸形,与这一疾病相关的SLC26A4基因与耳聋关系密切。线粒体DNAA1555G突变与氨基糖苷类抗生素导致耳聋有相关性,该突变检测有利于揭示药物性聋和环境因素的关系。我们对西北地区少数民族共1330例非综合征感音神经性聋患者,以PCR及直接测序检测SLC26A4基因第8、第19外显子的突变,运用PCR-RFLP筛查1ntDNA1555A>G点突变。在共1330例少数民族患者中,筛查出SLC26A4基因c.919-2A>G、c.2168A>G、c.2162C>T三种突变形式,检测到七种基因型,包括纯合26例,杂合40例,复合杂合突变5例,其中双等位基因的突变频率为2.33%。同期进行的本地区汉族457例聋人检测到6种基因型,包括纯合15例,杂合31例及复合杂合突变8例,双等位基因突变频率为5.03%。分析显示汉族同藏族、东乡族及维族的该基因突变频率有统计学差异,回族与东乡族和维族均有差异。研究证实c.919-2A>G突变是汉族聋人的热点突变,这一突变在汉族与藏族、东乡族及维吾尔族均存在统计学差异,维族与回族及哈萨克族有差异,回族与东乡族存在差异。研究中检测出mtDNA1555A>G突变的患者有28例,突变频率为2.11%,同地区457例汉族患者中突变者有32例,突变频率为7.00%,两者之间有显著性差异。在106例AAID患者中有9例检测到mtDNA1555A>G突变,AAID患者中突变频率为8.49%。各少数民族耳聋患者频率比较显示汉族与回族、东乡族及维吾尔族之间的突变频率存在统计学差异。研究证实SLC26A4基因在各少数民族与汉族的突变频谱不同,热点突变各异,因此需要针对各少数民族研究其突变频谱,制定适合各民族的基因诊断策略和产前诊断方法。研究表明有必要在本地区少数民族耳聋人群中开展mtDNA1555A>G突变的基因诊断,在散发耳聋患者、遗传性耳聋家系开展该突变检测,进行科学干预有助于延缓和减少药物性耳聋的发生。
第四章常染色体显性遗传非综合征耳聋家系的候选基因分析
遗传性疾病的基因定位克隆方法多样,需要根据遗传资源的特征选择合适的研究方法。本文旨在探索适宜于遗传性耳聋病因学研究的有效方法。针对一个遗传性耳聋大家系,我们系统进行临床资料和表型特点研究,并通过候选基因突变筛查方法,明确了该家系的致病基因。首先通过对家系中耳聋患者发病特点的分析,我们明确其遗传方式为常染色体显性遗传。总结本家系表型特点有：耳聋首先以高频听力损失为主,后期影响到全频听力,部分患者表现有前庭功能障碍的症状。通过对表型的详尽分析,研究中将候选基因局限在少数几个基因,进而对最符合表型特点的COCH基因全部外显子进行突变筛查,发现了该基因第8外显子c.485G>A突变为致病突变,该突变与家系中遗传性状共分离。研究中发现该家系中听力损失外显率为100%,听力损失随年龄增长而逐渐加重,前庭功能障碍的外显率为22.22%,前庭障碍症状与听力损失的程度没有相关性。从听力学特点和前庭功能障碍特征判断,该家系与梅尼埃病的临床表现不符。我们认为遗传性耳聋家系的基因定位克隆,首选位置克隆和候选基因克隆法,通过连锁分析能够定位耳聋相关基因的位置,候选基因克隆法具有经济快捷的优势。收集详实的临床资料和听力学资料、充分分析家系临床特征对于选择适宜的研究方法是十分必要的。
Hearing loss seriously affects the patients'function of audition and speech, which leads to the barriers of social communication. The high morbidity makes it a research hot issue in medical field. Since the first deafness gene was cloned in1995, more than40NSHL related genes have been found and molecular mechanism of deafness has been revealed. China is a big family, which contains56ethnic groups and has rich genetic resources especially from ancient minority ethnic groups. Therefore, it is necessary to carry out the research of deafness genes of ethnic minorities in China. This study aims to collect the deafness resources from ethnic minorities in the northwest China, and build a clinical and genetic resource library to cover major ethnic minorities in the northwest. Based on this, three types of high-risk deafness genes'molecular epidemiology research are carried out to reveal the relations of these genes and deafness,to explore the strategies for developing the deafness gene diagnosis and to find the ways to prevent deafness through human intervention. The main content of the research is comprised of four parts:
The first chapter:The construction of deaf resources library from ethnic minorities in northwest China.
The genetic resourceof Northwest minority deaf population is extremely scarce, and has a decreasing trend. We first design the standard process of the construction of the resources library. Then we collect deafness sporadic cases and deaf family resources, conduct questionnaire surveys, physical examination, audiological examination and family mapping, sign informed consent form and extract the peripheral venous blood, extract genomic DNA to establish a full set of libraty for digital management. We have collected1673deafness sporadic cases and146hereditary deafness families from ethnic minorities. It has accumulated resources for further genetic studies.We believe that protection of minority ethnic group deafness resources needs to be further strengthened, and a scientific and perfect resource libraty management system needs to be established.
The second chapter:Deafness related gene GJB2screening and diagnosis strategy research in the northwest ethnic minorities.
GJB2gene is the most common molecular etiology in congenital deafness. GJB2gene codes gap junction protein Cx26, which plays an important role in the inner ear electrolyte exchange and information transmission between cells, and is closely associated with human auditory function.We carry out GJB2gene's screening study in northwest minority deafness patients to analyze the epidemic condition of the gene, reveal the mutation hotspot of ethnic minorities and explore the genetic diagnosis strategy suitable for the deaf people.In this study, we finished1330ethnic minorities NSHL cases and457Han ethnic NSHL cases for GJB2gene mutation screening. The results showed that11mutation forms were found, including a new mutation:c.275C>G.202mutation or sequence change cases,75cases of homozygous mutations,92cases of heterozygous mutations and35cases of compound heterozygous mutations were found in ethnic minorities.The mutation frequency was15.19%(202/1330) in ethnic minorities and19.04%(87/457) in ethnic Han. It has no significant difference in allele frequency from ethnic minorities and ethnic Han. No differences were found between the ethnic groups except Uygur and Han.Frameshift mutation is the main form of GJB2gene in various ethnic groups. This gene type has determined that the hearing loss is either serious or profound.In ethnic minorities, c.235delC, c.35delG, c.109G>A and c.299-300delAT were the highest allele frequency forms. Different nations have different hotspots: Tibetan was c.235delC and c.109G>A; Dongxiang was c.299-300delAT and c.235delC; Hui ethnic was c.235delC and c.109G>A; Kazak was c.35delG; Uygur was c.235delC and c.35delG; Han ethnic was c.235delC, c.109G>A and c.299-300delAT.The research also showed that mutation frequency of each ethnic group was consistent with its ethnic background, especially in kazak and uighurs which has obvious Caucasus background.In this study, complete GJB2gene mutation spectrums of all ethnic groups were made, which could provide the methodology basis for personalized genetic diagnosis and widespread gene screening in all ethnic groups. Considering the structural characteristics and the dispersion of mutations, it is advisable to choose the diagnosis model of the whole coding sequence screening.
The third chapter:SLC26A4geneand mtDNAA1555G mutation screeningof non-syndrome sensorineural deafness in the northwest ethnic minorities.
Vestibular aqueduct expandingis the most common inner ear malformation.,SLC26A4gene which associated with vestibular aqueduct expanding is closely associated with deafness. mtDNAA1555G mutation associates with deafness caused by AmAn. The mutation detection is helpful to explore the relationship between drug deafness and environmental factors. In this study, we collected1330patients with NSHL from ethnic minorities in northwest China to carry out SLC26A4gene (8and9exons) and mtDNAA1555G mutation screening through PCR-RFLP or direct sequencing methods.In SLC26A4gene, three mutation forms have been found:919-2A>G, c.2168A>G and2162C>T. Seven genetypes were found in ethnic minorities, including26cases of homozygous,40cases of hybrid and5cases of compound heterozygous; six genetypes were found in ethnic Han, including15cases of homozygous,31cases of hybrid and8cases of compound heterozygous. The detection rates of homozygous and compound heterozygous mutations were2.33%(31/1330) and5.03%(23/457), respectively. The comparison of different ethnics showed that statistically significant differences had been found between ethnic Han and Tibetan, Dongxiang, Uighur. The difference also existed in ethnic Hui and Dongxiang and Uighur. The study also confirmed that919-2A>G allele frequencies had statistically significant differences between ethnic Han and Tibetan, Dongxiang, Uyghur; between Uighur and ethnic Hui, Kazak; and also between ethnic Hui and Dongxiang. In the study of mtDNA, we found that:28cases had mtDNAA1555G mutation in ethnic minorities, mutation frequency was2.11%(28/1330);32cases had mtDNAA1555G mutation in ethnic Han, mutation frequency was7.00%(32/457). Statistical processing showed that there was a significant difference between mutation frequency of ethnic minorities and ethnic Han.In106cases of AAID,9cases had mtDNAA1555G mutation and mutation frequency was8.49%.After statistical analysis, there is a statistically significant difference on mtDNAA1555G mutation frequency between Dongxiang and ethnic Han, and also between ethnic Hui and Uighur.The results showed that all the ethnic minorities have the unique spectrum of SLC26A4gene mutation, and the hotspots are not identical. We need to formulate genetic diagnosis strategy and choose the suitable methods of gene diagnosis and prenatal diagnosis for different ethnics; it is necessary to carry out the mtDNA1555A>G mutation genetic diagnosis in the region deafness people from ethnic minorities, which will help to slow down and reduce the occurrence of AAID.
The fourth chapter:Analysis of candidate genes in an Autosomal dominant non-syndrome hearing loss pedigree
There are many gene positional cloning methods for genetic disease. It is necessary to choose the appropriate research method according to the characteristics of the genetic resources. In this study, the purpose was to explore suitable and effective approach to the study of the hereditary deafness etiology.We carried out systematic research in clinical data and phenotypic characteristics of a hereditary deafness pedigree. Through candidate gene mutation screening, we made clear the pathogenic genes. Firstly, we defined the genetic way as autosomal dominant inheritance through the analysis of the onset of the characteristics of deafness patients. The phenotypic characteristics are summarized as:High frequency hearing loss was the first performance, and then the whole frequency hearing would be affected. Some patients had symptoms of vestibular function obstacle performance. Through the detailed analysis of the phenotype, candidate genes were confined to a handful of genes. And then we chose COCH gene which accord the most with the characteristics of phenotype to screen mutations in all exons. c.485G>A was found in exon8and mutated into pathogenic mutation. The mutation and deafness phenotype was in the line of separation.The study found that:the hearing loss penetrance was100%, which gradually aggravated with age; penetrance of vestibular dysfunction was22.22%, which was not associated with the degree of hearing loss. Judging from characteristics of audiological and vestibular function obstacle features, the family was not conforming to the clinical manifestations of Meniere's disease. We believe that the hereditary deafness family gene mapping, preferred position cloning and candidate gene cloning methods can locate the position of deafness genes through linkage analysis.Candidate gene cloning methodis economical, fast and convenient. Collecting detailed clinical data and audiology data, analyzing fully of clinical characteristics are indispensable for choosing appropriate research method.
引文
[1]韩东一.耳鼻咽喉头颈外科学发展现状及展望.解放军医学志,2011,36(11)：1127-1130.
[2]Morton CC,Nance WE.Newborn hearing screening-a silent revolution. N Engl J Med. 2006;354(20):2151-2164.
[3]第二次残疾人抽样调查办公室.全国第二次残疾人抽样调查主要数据手册.北京；华夏出版社,2007：2,38.
[4]王国建.耳聋基因诊断的临床实践.解放军军医进修学院博士论文,2008年
[5]胡浩,邬玲仟,梁德生,等.学语前性耳聋疾病相关基因的产前诊断.中华妇产科杂志,2005,40：591-594.
[6]韩明昱,楚严,卢彦平,等.孕期女性常见耳聋基因筛查与耳聋出生缺陷干预.中华耳科学杂志,2011,9(3)：289-295.
[7]骆为祥.少数民族人口分布及其变动分析.南方人口,2008,23(1)：42-50.
[8]Bayazit YA, Yilmaz M. An overview of hereditary hearing loss. ORL J Otorhinolaryngol Relat Spec.2006;68(2):57-63.
[9]《世界人类基因组与人权宣言》.联合国教科文组织第29届大会.1997年,巴黎.
[10]《世界医学协会赫尔辛基宣言》.第64届世界医学协会联合大会,福塔莱萨,巴西,2013年10月
[11]Miller, S.A., D.D. Dykes, and H.F. Polesky, A simple salting out procedure for extracting DNA from human nucleated cells. Nucl. Acids Res.,1988.16(3):p.1215.
[12]徐杰舜.中国民族关系发展大趋势论.学术探索.2011,10：55-63
[13]曹宗富,曹彦荣,马立广,等.中国人类遗传资源共享利用的标准化研究.遗传.2008,30(1)：51-58.
[14]Duman D,Mustafa Tekin. Autosomal recessive nonsyndromic deafness genes:a review. Front Biosci.2012,17:2213-2236.
[15]Zelante L, Gasparini P, Estivill X,et al. Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet.1997,6(9):1605-1609.
[16]Kelsell DP, Dunlop J, Stevens HP,et al. Connexin 26 mutations in hereditary nonsyndromic sensorineural deafness. Nature.1997,387(6628):80-83.
[17]Mhaske PV, Levit NA, Li L, et al. The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity. American Journal of Physiology:Cell Physiology.2013,304(12):1150-1158.
[18]de Zwart-Storm EA, van Geel M, Veysey E, et al. A novel missense mutation in GJB2, p.Tyr65His, causes severe Vohwinkel syndrome. Br J Dermatol.2011;164(1):197-199.
[19]Birkenhager R, Lublinghoff N, Prera E, et al. Autosomal dominant prelingual hearing loss with palmoplantar keratoderma syndrome:Variability in clinical expression from mutations of R75W and R75Q in the GJB2 gene. American Journal of Medical Genetics A.2010; 152(7):1798-1802.
[20]Guilford P, Ben Arab S, Blanchard S,et al. A non-syndrome form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat Genet.1994;6:24-28.
[21]Bruzzone R, White TW, Paul DL. Connections with connexins:the molecular basis of direct intercellular signaling. Eur J Biochem.1996;238(1):1-27.
[22]Nakagawa S, Maeda S, Tsukihara T. Structural and functional studies of gap junction channels.Current Opinion in Structural Biology.2010;20(4):423-430.
[23]Saez JC, Schalper KA, Retamal MA,et al. Cell membrane permeabilization via connexin hemichannels in living and dying cells. Experimental Cell Research.2010; 316(15): 2377-2389.
[24]Harris AL, Bevans CG. Exploring hemichannel permeability in vitro. Methods Mol Biol 2001;154:357-377.
[25]Mukherjee M, Phadke SR, Mittal B. Connexin 26 and autosomal recessive non-syndromic hearing loss. Indian J Hum Genet, 2003,9:40-50.
[26]Takada Y, Beyer LA, Swiderski DL,et al. Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy. Hear Res.2014;309:124-135.
[27]Cohen-Salmon M,Ott T,Michel V,et al.Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment andcell death. Curr Biol.2002;12(13):1106-1111.
[28]Wei Q, Huang H. Insights into the role of cell-cell junctions in physiology and disease. International Review of Cell and Molecular Biology.2013;306:187-221.
[29]Beltramello M, Piazza V, Bukauskas FF,et al. Impaired permeability to ins(1,4,5)p3 in a mutant connexin underlies recessive hereditary deafness. Nat Cell Biol.2005;7(1):63-69.
[30]Kikuchi T, Kimura RS, Paul DL,et al. Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis. Anat Embryol (Berl).1995;191(2):101-118.
[31]Lefebvre PP, Van De Water TR. Connexins, hearing and deafness:clinical aspects of mutations in the connexin 26 gene. Brain Res Brain Res Rev.2000;32(1):159-162.
[32]Kikuchi T, Kimura RS, Paul DL,et al. Gap junction systems in the mammalian cochlea. Brain Res Brain Res Rev.2000;32(1):163-166.
[33]Van Laer L, Cryns K, Smith RJ,et al. Nonsyndromic hearing loss. Ear Hear.2003;24(4):275-88.
[34]Wangemann P.K(+) cycling and its regulation in the cochlea and the vestibular labyrinth. Audiol Neurootol.2002;7(4):199-205.
[35]Bitner-Glindzicz M. Hereditary deafness and phenotyping in humans.Br Med Bull,2002, 63(1):73-94.
[36]Oguchi T, Ohtsuka A, Hashimoto S, et al. Clinical features of patients with GJB2 (connexin 26) mutations:severity of hearing loss is correlated with genotypes and protein expression patterns. J Hum Genet.2005;50(2):76-83.
[37]Ballana E,Ventayol M,Rabionet R,Gasparini P, Estivill X.Connexins and deafness homepage.http://davinci.crg.es/deafness/Accessed 5 March 2014.
[38]Hilgert N, Smith RJH, van Camp G. Forty-six genes causing nonsyndromic hearing impairment:which ones should be analyzed in DNA diagnostics? Mutation Research.2009;681(2-3):189-196.
[39]Van Camp G, Willems PJ, Smith RJ.Nonsyndromic hearing impairment:unparalleled heterogeneity. Am J Hum Genet.1997;60(4):758-764.
[40]Gasparini P, Rabionet R, Barbujani G, et al. High carrier frequency of the c.35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 c.35delG. Eur J Hum Genet.2000; 8(1):19-23.
[41]Park HJ, Hahn SH, Chun YM, et al.Connexin26 mutations associated with nonsyndromic hearing loss. Laryngoscope.2000;110(9):1535-1538.
[42]Kudo T, Ikeda K, Kure S, et al.Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population. Am J Med Genet.2000;90(2): 141-145.
[43]Liu Y, Ke X, Qi Y,et al. Connexin26 gene (GJB2):prevalence of mutations in the Chinese population. J Hum Genet.2002;47(12):688-690.
[44]Pu Dai, Fei Yu, Bing Han,et al. GJB2 mutation spectrum in 2063 Chinese patients with nonsyndromic hearing impairment. J Transl Med.2009; 7:26.
[45]Chen Y, Tudi M, Sun J,et al. Genetic mutations in non-syndromic deafness patients of Uyghur and Han Chinese ethnicities in Xinjiang, China:a comparative study. J Transl Med.2011;9:154.
[46]Chen K, Zong L, Liu M,et al. Developing regional genetic counseling for southern Chinese with nonsyndromic hearing impairment:a unique mutational spectrum. J Transl Med.2014;12:64.
[47]Dai P, Yu F, Han B, et al. The prevalence of the c.235delC GJB2 Mutation in a Chinese Deaf Population. Genet Med.2007; 9(5):283-289.
[48]于飞,戴朴,韩东一.GJB2基因突变及语前遗传性非综合征性耳聋.国外医学耳鼻咽喉科学分册,2005,29：359-361.
[49]Ohtsuka A, Yuge I, Kimura S,et al. GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. Hum Genet. 2003;112(4):329-333.
[50]Yan D, Park HJ, Ouyang XM,et al. Evidence of a founder effect for the c.235delC mutation of GJB2 (connexin 26) in east Asians. Hum Genet.2003;114(1):44-50.
[51]Van Laer L, Coucke P, Mueller RF, et al. A common founder for the c.35delG GJB2 gene mut ation in connexin 26 hearing impairent. J Med Genet.2001,38(8):515-518.
[52]Jun AI,McGuirt WT,Hinojosa R,et al. Temporal bone histopathology in connexin 26-related hearing loss. Laryngoscope.2000,110 (2 Pt 1):269-275.
[53]Chan DK, Schrijver 1, Chang KW.Diagnostic yield in the workup of congenital sensorineural hearing loss is dependent on patient ethnicity. Otol Neurotol.2011;32(1): 81-87.
[54]Tsukada K, Nishio S, Usami S.A large cohort study of GJB2 mutations in Japanese hearing loss patients. Clin Genet.2010;78(5):464-470.
[55]Han SH, Park HJ, Kang EJ, et al. Carrier frequency of GJB2 (connexin-26) mutations causing nherited deafness n the Korean population. J Hum Genet.2008;53(11-12):1022-1028.
[56]Kim SY, Lee BY, Lim JH,et al.Determination of the carrier frequencies of selected GJB2 mutations in the Korean population. Int J Audiol.2011;50(10):694-698.
[57]Kelley PM, Harris DJ, Comer BC,et al. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet.1998;62(4):792-799.
[58]Chan DK, Schrijver I, Chang KW.Connexin-26-associated deafness:phenotypic variability and progression of hearing loss. Genet Med.2010; 12(3):174-181.
[59]Xiao ZA, Xie DH. GJB2 (Cx26) gene mutations in Chinese patients with congenital sensorineural deafness and a report of one novel mutation. Chin Med J (Engl).2004; 117(12):1797-1801.
[60]贺定华,冯永,夏昆,等.GJB2基因在遗传性聋中的检测.听力学及言语疾病杂志,2005,13(5)：301-303.
[61]Palmada M, Schmalisch K, Bohmer C, et al.Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. Neurobiol Dis.2006;22(1): 112-118.
[62]Huculak C,Bruyere H,Nelson TN,et al.V37I connexin 26 allele in patients with sensorineural hearing loss:evidence of its pathogenicity. Am J Med Genet A.2006;140(22): 2394-2400.
[63]Schrijver I, Chang KW.Two patients with the V37I/c.235delC genotype:are radiographic cochlear anomalies part of the phenotype? Int J Pediatr Otorhinolaryngol2006;70(12): 2109-2113.
[64]Lei Li,Jingrong Lu, Zheng Tao,et al. The p.V37I Exclusive Genotype Of GJB2:A Genetic Risk-Indicator of Postnatal Permanent Childhood Hearing Impairment.PLoS One.2012; 7(5):e36621.
[65]Wilcox SA,Saunders K,Osborn AH,et al.High frequency hearing loss correlated with mutations in the GJB2 gene. Hum Genet.2000;106(4):399-405.
[66]Bruzzone R, Veronesi V, Gomes D,et al.Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett.2003.533(1-3): 79-88.
[67]Jara O, Acuna R, Garcia IE, et al.Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function. Mol Biol Cell.2012;23(17):3299-3311.
[68]Wattanasirichaigoon D,Limwongse C,Jariengprasert C,et al. High prevalence of V37I genetic variant in the connexin-26 (GJB2) gene among non-syndromic hearing-impaired and control Thai individuals. Clin Genet.2004;66(5):452-460.
[69]Abe S, Usami S, Shinkawa H,et al. Prevalent connexin 26 gene (GJB2) mutations in Japanese. J Med Genet.2000;37(1):41-43.
[70]Gualandi F, Ravan iA, Berto A, et al. Exploring the clinical and epidemiological complexity of GJB2-linked deafness. Am J Med Genet.2002;112(1):38-45.
[71]Snoeckx RL, Huygen PL, Feldmann D,et al.GJB2 mutations and degree of hearing loss:a multi-center study. Am J Hum Genet.2005;77(6):945-957.
[72]Cryns K, Orzan E, Murgia A, et al.A genotype-phenotype correlation for GJB2(connexin 26) deafness. J Med Genet.2004;41(3):147-154.
[73]Feng Xin, Yongyi Yuan, Xiaoming Deng,et al. Genetic mutations in nonsyndromic deafness patients of Chinese minority and han ethnicities in Yunnan, China. J Transl Med.2013; 11:312.Published online Dec 17,2013.
[74]yubin Ji, dongyi Han, Ian Lan,et al. Molecular epidemiological analysis of mitochondrial DNA 12SrRNA A1555G,GJB2, and SLC26A4 mutations in sporadic outpatients with nonsyndromic sensorineural hearing loss in China. Acta Otolaryngol.2011; 131(2):124-129.
[75]Yongyi Yuan,Yiwen You, Deliang Huang,et al.Comprehensive molecular etiology analysis of nonsyndromic hearing impairment from typical areas in China.J Transl Med.2009;7:79.
[76]马虎成.《撒尔塔：一个曾经被忽略的民族名称》(上)、(下).《西北民族研究》1992(2),55-64.
[77]Nina Danilenko, Elena Merkulava, Marina Siniauskaya,et al. Spectrum of Genetic Changes in Patients with Non-Syndromic Hearing Impairment and Extremely High Carrier Frequency of c.35delG GJB2 Mutation in Belarus. PLoS One.2012; 7(5):e36354.
[78]Downs MP. Universal newborn hearing screening-the Colorado story. Int J Pediatr Otorhinolaryngol.1995;14:257-259.
[79]Mehl AL, Thomson V. The Colorado newborn hearing screening project,1992-1999:on the threshold of effective population-based universal newborn hearing screening. Pediatrics.2002;14:E7.
[80]Tom Walsh,Sarah B. Pierce,Danielle R. Lenz,et al. Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51.Am J Hum Genet.2010,87(l):101-109.
[81]郭玉芬,关静,徐百成,等.甘肃省盲聋哑学校283名聋哑学生的病因分析.中华耳科学杂 志;,2006,4(1):30-33.
[82]Morton NE. Genetic epidemiogy of hearing impairment. Ann NY Acad Sci.1991;14:16-31.
[83]A. Eliot Shearer and Richard J.H. Genetics:advances in genetic testing for deafness.PMC, Curr Opin Pediatr.2012,24(6):679-686.
[84]Nance WE. The genetics of deafness. Ment Retard Dev Disabil Res Rev.2003,8:109-119.
[85]Bamiou DE, Phelps P, Sirimanna T. Temporal bone computed tomography findings in bilateral sensorineural hearing loss. Arch Dis Child.2000;82(3):257-260.
[86]Mafong DD, Shin EJ, Lalwani AK. Use of laboratory evaluation and radiologic imaging in the diagnostic evaluation of children with sensorineural hearing loss.Laryngoscope.2002;112(1):1-7.
[87]Wu CC, Chen YS, Chen PJ, et al. Common clinical features of children with enlarged vestibular aqueduct and Mondini dysplasia. Laryngoscope.2005;115(1):132-137.
[88]Antonelli P,Varela A,Mancuso A.Diagnostic yield of high-resolution computed tomography for pediatric sensorineural hearing loss. Laryngoscope.1999; 109:1642-1647.
[89]Valvassori G, Clemis J. The large vestibular aqueduct syndrome. Laryngoscope.1978;88:273-278.
[90]Madden C, Halsted M, Meinzen-Derr J,et al. The influence of mutations in the SLC26A4 gene on the temporal bone in a population with enlarged vestibular aqueduct. Arch Otolaryngol Head Neck Surg.2007; 133(2):162-168.
[91]Phelps PD, Coffey RA, Trembath RC,et al. Radiological malformations of the ear in Pendred syndrome. Clin Radiol.1998;53:268-273.
[92]Chen A, Francis M, Ni L, et al.:Phenotypic manifestations of branchio-oto-renal syndrome. Am J Med Genet 1995;58:365-370.
[93]Madden C, Halsted MJ, Hopkin RJ, et al.Temporal bone abnormalities associated with hearing loss in Waardenburg syndrome. Laryngoscope.2003;113:2035-2041.
[94]Everett LA, Glaser B, Beck JC,et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet.1997;17:411-422.
[95]Li XC, Everett LA, Lalwani AK,et al. A mutation in PDS causes non-syndromic recessive deafness. Nat Genet.1998; 18:215-217.
[96]杨伟炎,张素珍,赵承君,等.95例大前庭水管综合征的临床分析.中华耳鼻咽喉科杂志，2003：38：191一194.
[97]Campbell C, Cucci RA, Prasad S,et al. Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutation and possible genotype-phenotype correlations. Hum Mutat.2001;14:404-411.
[98]Azaiez H, Yang T, Prasad S,et al. Genotype-phenotype correlations for SLC26A4-related deafness. Hum Genet.2007;122(5):451-457.
[99]Scott D, Wang R, Kreman T,et al.Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and nonsyndromic hearing loss (DFNB4). Hum Mol Genet.2000;9:1709-1715.
[100]Saier MH J,Zhai Yr. A web-based program (WHAT) for the simultaneous prediction of hydropathy, amphipathicity, secondary structure and transmembrane topology for a single protein sequence. J Mol Microbiol Biotechnol.2001;3(4):501-502.
[101]Lorraine A. Everett, Hakim Morsli, Doris K. Wu,et al. Expression pattern of the mouse ortholog of the Pendred's syndrome gene (Pds) suggests a key role for pendrin in the inner ear. Proc Natl Acad Sci U S A.1999; 96(17):9727-9732.
[102]Yoshino T, Sato E, Nakashima T, Teranishi M,et al. Distribution of pendrin in the organ of corti of mice observed by electron immunomicroscopy. Eur Arch Otorhinolaryngol.2006;263:699-704.
[103]Wangemann P, Nakaya K, Wu T,et al. Loss of cochlear HCO3-secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model. Am J Physiol Renal Physiol.2007;292(5):F1345-53.
[104]Everett LA, Belyantseva IA, Noben-Trauth K, et al.Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. Hum Mol Genet.2001;10:153-161.
[105]Scott DA, Wang R, Kreman TM,et al. The Pendred syndrome gene encodes a chloride-iodide transport protein. Nat Genet.1999;21(4):440-443.
[106]Park HJ, Shaukat S, Liu XZ,et al. Origins and frequencies of SLC26A4 (PDS) mutations in East and South Asians:glogal implications for the epidemiology of deafness. J Med Genet.2003;40:242-248.
[107]Van Hauwe P, Everett LA, Coucke P,et al. Two frequent missense mutations in pendred syndrome. Hum Mol Genet.1998;7:1099-1104.
[108]Coyle B, Reardon W, Herbrick JA,et al. Molecular analysis of the PDS gene in Pendred syndrome. Hum Mol Genet.1998;7:1105-1112.
[109]Alejandra Pera,Silvia Dossena,Simona Rodighiero,et al. Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA. Proc Natl Acad Sci USA.2008; 105(47):18608-18613.
[110]Tsukamoto K, Suzuki H, Harada D,et al. Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct:a unique spectrum of mutations in Japanese. Eur J Hum Genet.2003; 14:916-922.
[111 Wang QJ, Zhao YL, Rao SQ, et al. A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China. Clin Genet.2007;72:245-254.
[112]Wu CC, Yeh TH, Chen PJ, et al. Prevalent SLC26A4 mutations in patients with enlarged vestibular aqueduct and/or Mondini dysplasia:a unique spectrum of mutations in Taiwan, including a frequent founder mutation. Laryngoscope.2005; 115:1060-1064.
[113]Hu X, Liang F, Zhao M,et al. Mutational analysis of the SLC26A4 gene in Chinese sporadic nonsyndromic hearing-impaired children. Int J Pediatr Otorhinolaryngol.2012;76:1474-1480.
[114]Mark van der Giezen, Jorge Tovar.Degenerate mitochondria.EMBO Rep.2005,6(6): 525-530.
[115]Patrick Francis Chinnery,Gavin Hudson. Mitochondrial genetics. Br Med Bull. Jun 2013,106(1):135-159.
[116]Schaefer AM,Taylor RW,Turnbull DM,et al.The epidemiology of mitochondrial disorders - past, present and future. Biochim Biophys Acta.2004,1659:115-120.
[117]Andrews RM, Kubacka I, Chinnery PF, et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet.1999,23:147.
[118]Temperley R, Richter R, Dennerlein S, et al. Hungry codons promote frameshifting in human mitochondrial ribosomes. Science.2010,327:301.
[119]Sutovsky P. Ubiquitin-dependent proteolysis in mammalian spermatogenesis, fertilization, and sperm quality control:killingthree birds with one stone. Microsc Res Tech.2003,61(1):88-102.
[120]Birky CW, Jr The inheritance of genes in mitochondria and chloroplasts:laws, mechanisms, and models. Annu Rev Genet.2001,35:125-148.
[121]Jochen Schacht, Andra E. Talaska, Leonard P. Rybak. Cisplatin and Aminoglycoside Antibiotics:Hearing Loss and Its Prevention.Anat Rec (Hoboken).2012,295(11):1837-1850.
[122]丁大连,金晓杰,赵纪余.卡那霉素在耳蜗毛细胞中的积聚部位.中华耳鼻咽喉科杂志,1997,32：348-349.
[123]Swan SK. Aminoglycoside nephrotoxicity. Semin Nephrol.1997,17(1):27-33.
[124]Jing Xie, Andra E. Talaska, Jochen Schacht. New developments in aminoglycoside therapy and ototoxicity.Hear Res.2011,281(1-2):28-37.
[125]Prezant TR,Aga Pian JV,Bohlman MC,et al. mitochondria ribosomal RNA mutation associatedwithbothantibiotie - indueedandnon syndromie dealness. Nat Genet. 1993,4(3):289 -294.
[126]De Rijk P, De Wachter R. RnaViz, a program for the visualisation of RNA secondary structure. Nucleic Acids Res.1997,25(22):4679-4684.
[127]Lu JX, Li ZY, Zhu Y,et al. Mitochondrial 12S rRNA variants in 1642 Han Chinese pediatricsubjects with aminoglycoside-induced and nonsyndromic hearing loss. Mitochondrion.2010,10(4):380-390.
[128]Hutchin T.Sensorineural hearing loss and the 1555G mitochondrial DNA mutation. Acta Otolaryngol.1999,119(1):48-52.
[129]Ouyang XM. Yan D. YH Dai P, et al. The genetic bases for non-syndromic hearing loss among Chinese. J Hum Genet.2009,54:131-140.
[130]Ying-Chang Lu, Chen-Chi Wu, Ting-Hua Yang, et al. Differences in the Pathogenicity of the p.H723R Mutation of the Common Deafness-Associated SLC26A4 Gene in Humans and Mice.PLoS One.2013; 8(6):e64906.
[131]Yang JJ, Tsai CC, Hsu HM, et al. Hearing loss associated with enlarged vestibular aqueduct and Mondini dysplasia is caused by splice-site mutation in the PDS gene. Hear Res.2005;199:22-30.
[132]Park HJ, Lee SJ, Jin HS, et al. Genetic basis of hearing loss associated with enlarged vestibular aqueducts in Koreans. Clin Genet.2005;67(2):160-165.
[133]穆豪放,陈峰,熊新,等.中国青海藏族、汉族mtDNA控制区遗传多态性.法医学杂志.2008,24(6)：417-422.
[134]to T, Choi BY, King KA, Zalewski CK,et al.SLC26A4 genotypes and phenotypes associated with enlargement of the vestibular aqueduct. Cell Physiol Biochem.2011;28(3):545-552.
[135]Boston M, Halsted M, Meinzen-Derr J,et al. The large vestibular aqueduct: a new definition based on audiologic and computed tomography correlation. Otolaryngol Head Neck Surg.2007;136(6):972-977.
[136]Pryor SP, Madeo AC, Reynolds JC,et al. SLC26A4/PDS genotype-phenotype correlation in hearing oss with enlargement of the vestibular aqueduct(EVA):evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities. J Med Genet.2005 Feb;42(2):159-65.
[137]Hutchin TP, Thompson KR, Parker M,et al. Prevalence of mitochondrial DNA mutations in childhood/congenital onset non-syndromal sensorineural hearing impairment. J Med Genet.2001,38(4):229-231.
[138]VALERIA GUARAN, LAURA ASTOLFI, ALESSANDRO CASTIGLIONE,et al. Association between idiopathic hearing loss and mitochondrial DNA mutations:A study on 169 hearing-impaired subjects. Int J Mol Med.2013,32(4):785-794.
[139]Richard J, Vivero,Xiaomei Ouyang, Denise Yan,et al. Mitochondrial DNA Mutation Screening in an Ethnically Diverse Nonsyndromic Deafness Cohort. Genet Test Mol Biomarkers.2012,16(9):1146-1148.
[140]Tessa A, Giannotti A, Tieri L, et al. Maternally inherited deafness associated with a T1095C mutation in the mDNA. Eur J Hum Genet,2002,9(2):147-149.
[141]Usami SI, Abe S, Akita J, et al. Prevalence of mitochondrial gene mutations among hearing impaired patients.J Med Genet.2000,37(1):38-40.
[142]Guan MX. Mitochondrial 12S rRNA mutations associated with aminoglycoside ototoxicity.Mitochondrion.2011,11(2):237-245.
[143]谢小冬,陕雪梅.回族起源的DNA证据.回族研究.2002,(3)：75-78.
[144]Yao YG, Kong QP, Wang CY,et al. Different matrilineal contributions to genetic structure of ethnic groups in the silk road region in china. Mol Biol Evol.2004,21(12):2265-2280.
[145]Guan MX, Yan Q, Li X, et al. Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deaf-ness-associated mitochondrial 12S ribosomal RNA mutations. Am J Hum Genet.2006,79:291-302.
[146]龚莎莎,郑静,张婷,等.氨基糖苷类抗生素耳毒性相关的线粒体DNA突变.国际遗传学杂志.2011,34(4)：202-212.
[147]管敏鑫,赵立东.与氨基糖菅类抗生素耳毒性相关的线粒体12SrRNA突变的流行病学特征,中华耳科学杂志.2006,4(2)：98-105.
[148]Fischel-Ghodsian N, Prezant TR, Chaltraw WE,et al. Mitochondrial gene mutation is a significant predisposing factor in aminoglycoside ototoxicity. Am J Otolaryngol. 1997,18(3):173-178.
[149]Zhao H, Young WY, Yan Q, et al. Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with amino-glycoside-induced and non-syndromic hearing loss. Nucleic Acids Res.2005,33:1132-1139.
[150]X Estivill, N Govea, E Barcelo,et al. Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides. Am J Hum Genet.1998,62(1):27-35.
[151]Fraser GR. Association of congenital deafness with goiter (Pendred's syndrome):a study of 207 families. Ann Hum Genet.1965; 14:201-249.
[152]Stinckens C, Huygen PL, Joosten FB,et al. Fluctuant, progressive hearing loss associated with Meniere like vertigo in three patients with the Pendred syndrome. Int J Pediatr Otorhinolaryngol.2001;14:207-215.
[153]Cremers CW, Admiraal RJ, Huygen PL,et al. Progressive hearing loss, hypoplasia of the cochlea and widened vestibular aqueducts are very common features in Pendred's syndrome. Int J Pediatr Otorhinolaryngol.1998;14:113-123.
[154]Xing M, Tokumaru Y, Wu G,et al. Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis. Cancer Res.2003;63(9):2312-2315.
[155]Jackler RK, de la Cruz A.The large vestibular aqueduct syndrome. Laryngoscope. 1989;14:1238-1243.
[156]Arcand P, Desrosiers M, Dube J,et al. The large vestibular aqueduct syndrome and seisorineural hearing loss in the pediatric population. J Otolaryngol.1991;14:247-250.
[157]Okumura T, Takahashi H, Honjo I, et al. Sensorineural hearing loss in patients with large vestibular aqueduct. Laryngoscope.1995;14:289-294.
[158]Mamikodlu B, Bentz B, Wiet RJ. Large vestibular aqueduct syndrome presenting with mixed hearing loss and an intact mobile ossicular chain. Otorhinolaryngol Nova.2000; 10:204-206.
[159]Saumil N. Merchant, Hideko H. Nakajima, Christopher Halpin,et al. Clinical Investigation and Mechanism of Air-Bone Gaps in Large Vestibular Aqueduct Syndrome. Ann Otol Rhinol Laryngol.2007; 116(7):532-541.
[160]Saumil N. Merchant, John J. Rosowski.Conductive Hearing Loss Caused by Third-Window Lesions of the Inner Ear. Otol Neurotol.2008; 29(3):282-289.
[161]David N. Cooper,Michael Krawczak, Constantin Polychronakos,et al. Where genotype is not predictive of phenotype:towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet.2013; 132:1077-1130.
[162]Lu J, Qian Y, Li Z, et al. Mitochondrial haplotypes may modulate the phenotypic manifestation of the deafness-associated 2S rRNA 555A>G mutation. Mitochondrion.2010,10:69-81.
[163]Reid FM, Vernham GA, Jacobs HT. A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum Mutat.1994,3:243-247.
[164]Zhao H, Li RH,Wang QJ,et al. Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family. Am J Hum Genet.2004,74(l):139-152.
[165]Rodriguez-Ballesteros M, Olarte M, Aguirre LA,et al. Molecular and clinical characterisation of three Spanish families with maternally inherited non-syndromic hearing loss caused by the 1494C>T mutation in the mitochondrial 12S rRNA gene. J Med Genet.2006,43(11e54.
[166]Chen J, Yang L, Yang A,et al.Maternally inherited aminoglycoside-induced and nonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees. Gene.2007,401(1-2):4-11.
[167]Nadol JB Jr. Hearing loss. N Engl J Med.1993;329(15):1092-1102.
[168]Steel KP. Science, medicine, and the future:New interventions in hearing impairment. BMJ,2000,320(7235):622-625.
[169]Chatterjee A,Jalvi R, Pandey N,Rangasayee R,et al. A novel locus DFNA59 for autosomal dominant nonsyndromic hearing loss maps at chromosome 11p14.2-q12.3. Hum Genet.2009;124(6):669-675.
[170]Leon PE, Raventos H, Lynch E,et al.The gene for an inherited form of deafness maps to chromosome 5q31. Proc Natl Acad Sci U S A.1992;89(11):5181-5184.
[171]Cheng J,Zhu Y, He S,et al.Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64. Am J Hum Genet.2011,89(1):56-66.
[172]Van Camp G, Smith R J H. Hereditary hearing loss homepage.World Wide Web URL: http://dnalab-www.uia.ac.be/dnalab/hhh/,Last updated:April 29,2014.
[173]Manolis EN, Yandavi N, Nadol JB, et al.A gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12-13.Hum Molec Genet.1996;5(7):1047-1050.
[174]Robertson NG,Lu L,Heller S,et al.Mutations in a novel cochlear gene cause DFNA9,a human nonsyndromic deafness with vestibular dysfun ction. Nat Genet.1998;20(3):299-303.
[175]Fransen E, Van Camp G. The COCH gene:a frequent cause of hearing impairment and vestibular dysfunction? Br J Audio,1999,33(5):297-302.
[176]Robertson NG, Skvorak AB, Yin Y, et al. Mapping and characterization of a novel cochlear gene in human and in mouse:a positional candidate gene for a deafness disorder, DFNA9. Genomics.1997;46(3):345-354.
[177]Robertson NG, Resendes BL, Lin JS,et al.Inner ear localization of mRNA and protein products of COCH, mutated in the sensorineural deafness and vestibular disorder, DFNA9. Hum Mol Genet.2001;10(22):2493-2500.
[178]Khetarpal U, Schuknecht HF, Gacek RR,et al. Autosomal dominant sensorineural hearing loss. Pedigrees, audiologic findings, and temporal bone findings in two kindreds. Arch Otolaryngol Head Neck Surg.1991; 117(9):1032-1042.
[179]kezono T, Omori A, Ichinose S, et al. Identification of the protein product of the Coch gene (hereditary deafness gene) as the major component of bovine inner ear protein. Biochim Biophys Acta,2001,1535(3):258-265.
[180]Robertson NG, Hamaker SA, Patriub V, et al. Subcellular localisation, secretion, and post-translational processing of normal Cochlin, and of mutants causing the sensorineural deafness and vestibular disorder, DFNA9. J Med Genet,2003,40(7):479-486.
[181]Makishima T, Rodriguez CI, Robertson NG, et al. Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder. Hum Genet,2005,118(1):29-34.
[182]Merchant SN, Linthicum FH, Nadol JB Jr. Histopathology of the inner ear in DFNA9. Adv Otorhinolaryngol,2000,56:212-217.
[183]Khetarpal U. Autosomal dominant sensorineural hearing loss. Further temporal bone findings. Arch Otolaryngol Head Neck Surg.1993,119(1):106-108.
[184]Bom SJ, De Leenheer EM, Lemaire FX,et al. Speech recognition scores related to age and degree of hearing impairment in DFNA2/KCNQ4 and DF-NA9/COCH. Arch Otolaryngol Head Neck Surg.2001; 127(9):1045-1048.
[185]Verhagen WIM, Bom SJH, Fransen E, et al. Hereditary cochleovestibular dysfunction due to a COCH gene mutation (DFNA9):a follow-up study of a family. Clin Otolaryngol, 2001,26(6):477-483.
[186]De Kok YJM, Bom SJH, Brunt TM, et al. A Pro51 Ser mutation in the COCH gene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects. Hum Molec Genet,1999,8(2):361-366.
[187]Fransen E, Verstreken M, Verhagen WIM, et al. High prevalence of symptoms of Meniere's disease in three families with a mutation in the COCH gene. Hum Mol Genet, 1999,8(8):1425-1429.
[188]Kamarinos M, McJill J, Lynch M, et al. Identification of a novel COCH mutation, I109N, highlights the similar clinical features observed in DFNA9 families. Hum Mutat, 2001,17(4):351.
[189]Fransen E, Verstreken M, Bom SJH, et al. A common ancestor for COCH related cochleovestibular (DFNA9) patients in Belgium and The Netherlands bearing the P51S mutation. J Med Genet,2001,38(1):61-64.
[190]Usami S, Takahashi K, Yuge I, et al. Mutations in the COCH gene are a frequent cause of autosomal dominant progressive cochleo-vestibular dysfunction, but not of Meniere's disease. Eur J Hum Genet,2003,11(10):744-748.
[191]Nagy I, Horvath M, Trexler M, et al. A novel COCH mutation, V104del, impairs folding of the LCCL domain of cochlin and causes progressive hearing loss. J Med Genet,2004,41: e9.
[192]Street VA, Kallman JC, Robertson NG, et al. A novel DFNA9 mutation in the vWFA2 domain of COCH alters a conserved cysteine residue and intrachain disulfide bond formation resulting in progressive hearing loss and site-specific vestibular and central oculomotor dysfunction. Am J Med Genet A,2005,139(2):86-95.
[193]Collin RWJ, Pauw RJ, Schoots J, et al. Identification of a novel COCH mutation, G87W, causing autosomal dominant hearing impairment (DFNA9). Am J Med Genet A,2006,140 (16):1791-1794.
[194]Chen DY, Chai YC, Yang T,et al. Clinical characterization of a novel COCH mutation G87V in a Chinese DFNA9 family. Int J Pediatr Otorhinolaryngol.2013;77(10):1711-1715.
[195]Pauw RJ, Huygen PL, Colditz GM,et al. Phenotype analysis of an Australian DFNA9 family with the 1109N COCH mutation. Ann Otol Rhinol Laryngol.2011;120(6):414-21.
[196]Hildebrand MS, Gandolfo L, Shearer AE,et al. A novel mutation in COCH-implications for genotype-phenotype correlations n DFNA9 hearing oss. Laryngoscope.2010; 120(12):2489-2493.
[197]Sun Q, Yang SZ, Kang DY,et al.Mutation screening of the COCH gene in familial and sporadic patients with late onset nonsyndromic sensorineural hearing loss among Chinese population. Zhonghua Yi Xue Za Zhi.2007;87(44):3107-3110.
[198]Cho HJ, Park HJ, Trexler M,et al. A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain. J Mol Med (Berl).2012;90(11):1321-1331.
[199]Gao J, Xue J, Chen L,et al. Whole exome sequencing identifies a novel DFNA9 mutation, C162Y. Clin Genet.2013;83(5):477-481.
[200]刘万清,博邵春,贺林.解码生命[M].北京：科学出版社,2000.
[201]孙悍军.常染色体显性遗传非综合征型耳聋基因定位克隆.解放军军医进修学院博十论文，2005年.
[202]Robertson NG, Cremers CW, Huygen PL,et al. Cochlin immunostaining of inner ear pathologic deposits and proteomic analysis in DFNA9 deafness and vestibular dysfunction. Hum Mol Genet.2006;15(7):1071-1085.
[203]Yuan HJ, Han DY, Sun Q,et al. Novel mutations in the vWFA2 domain of COCH in two Chinese DFNA9 families. Clin Genet.2008;73(4):391-394.
[204]Kommareddi PK, Nair TS, Raphael Y, et al. Cochlin isoforms and their interaction with CTL2 (SLC44A2) in the inner ear. J Assoc Res Otolaryngol 2007,8:435-446.
[205]Yao J, Py BF, Zhu H, Bao J, Yuan J. Role of protein misfolding in DFNA9 hearing loss. J Biol Chem 2010;285:14909-14919.
[206]Verstreken M, Declau F, Wuyts F L,et al. Hereditary otovestibular dysfunction and Meniere's disease in a large Bel-gian family is caused by a missense mutation in the COCH gene. Otology & Neurotology,2001,22 (6):874-881.
[207]Kemperman M H, De Leenheer M R, Huygen P L.et al. Audiometric, vestibular, and genetic aspects of a DFNA9 family with a G88E COCH Mutation. Otology & Neurotology,2005,26 (5):926-933.
[208]Committee on Hearing and Equilibrium.Guidelines for the diagnosis and evaluation of therapy in Meniere's disease[J].Otolaryngol Head Neck Surg,1995,113:181.
[209]Morrison AW. On genetic and environmental factors in Meniere's disease. Am. J. Otol.1994;15(1):35-39.
[210]Morrison AW, Bailey ME, Morrison GA.Familial Meniere's disease:clinical and genetic aspects. J Laryngol Otol.2009;123(1):29-37.
[211]孙燕,刘博,戴海江,等.梅尼埃病患者COCH(?)基因第4和5外显子突变研究[J].中华医学杂志,2005,85(5)：345-347.
[212]Irene Gazquez,Jose A Lopez-Escamez. Genetics of Recurrent Vertigo and Vestibular Disorders. Curr Genomics.2011; 12(6):443-450.
[213]Ali M. Waryah, Zubair M. Ahmed, et al.Molecular and Clinical Studies of X-linked Deafness Among Pakistani Families.J Hum Genet. J Hum Genet.2011;56(7):534-540.
[214]Zina ZB, Masmoudi S, Ayadi H, et al. From DFNB2 to Usher syndrome:variable expressivity of the same disease. Am. J. Med. Genet,2001,101(2):181-183.
[215]Baldwin CT, Weiss S, Farrer LA, et al. Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle Eastern Druze population. Hum. Mol.Genet.1995,4(9):1637-1642.
1. Nadol JB Jr. Hearing loss. N Engl J Med.1993;329(15):1092-1102.
2. Steel KP. Science, medicine, and the future:New interventions in hearing impairment. BMJ, 2000,320(7235):622-625.
3. Van Camp G, Willems PJ, Smith RJ.Nonsyndromic hearing impairment:unparalleled heterogeneity. Am J Hum Genet.1997;60(4):758-764.
4. Chatterjee A,Jalvi R, Pandey N,Rangasayee R,et al. A novel locus DFNA59 for autosomal dominant nonsyndromic hearing loss maps at chromosome 11p14.2-q12.3. Hum Genet.2009;124(6):669-675.
5. Gorlin RJ, Toriello HV, Cohen MM. Hereditary Hearing Loss and its Syndromes. Oxford University Press; New York:1995. pp.3-4.
6. Cranefield PF, Federn W. Paulus Zacchias on mental deficiency and on deafness. Bull N Y Acad ed.170;46:3-21.
7. Dow GS, Poynter CI. The Dar family. Eugen News.1930;15:128-130.
8. Van Camp G, Smith RJH. Hereditary Hearing Loss Homepage.2010 http://hereditaryhearingloss.org. Update:1.10.2010.
9. Leon PE, Raventos H, Lynch E, Morrow J, King MC. The gene for an inherited form of deafness maps to chromosome 5q31. Proc Natl Acad Sci U S A.1992;89:5181-5184.
10. Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, King MC. Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science.1997;278:1315-1318.
11. Guilford P, Ben Arab S, Blanchard S, Levilliers J, Weissenbach J, Belkahia A, Petit C. A non-syndrome form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat Genet.1994;6:24-28.
12. Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM. Connexin 26 mutations n hereditary non-syndromic sensorineural deafness. Nature.1997;387:80-83.
13. Kenneson A, Van Naarden Braun K, Boyle C. GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss:a HuGE review. Genet Med.2002;4:258-274.
14. de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, Huber I, Monaco AP, Malcolm S, Pembrey ME, Ropers HH, Cremers FP. Association between X-linked mixed deafness and mutations in the POU domain genePOU3F4. Science.1995;267:685-688.
15. Gorlin RJ, Toriello HV, Cohen MM. Hereditary Hearing Loss and its Syndromes. Oxford University Press; New York:
16. Lenz DR1, Avraham KB. Hereditary hearing loss:from human mutation to mechanism. Hear Res.2011;281(1-2):3-10.
17. Phelps PD, Coffey RA, Trembath RC,et al. Radiological malformations of the ear in Pendred syndrome. Clin Radiol.1998;53:268-273.
18. Everett LA, Glaser B, Beck JC,et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet.1997; 17:411-422.
19. Campbell C, Cucci RA, Prasad S,et al. Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutation and possible genotype-phenotype correlations. Hum Mutat.2001;14:404-411.
20. Scott DA, Wang R, Kreman TM,et al. The Pendred syndrome gene encodes a chloride-iodide transport protein. Nat Genet.1999;21(4):440-443.
21. Azaiez H, Yang T, Prasad S,et al. Genotype-phenotype correlations for SLC26A4-related deafness. Hum Genet.2007; 122(5):451-457.
22. S Chatkupt, S Chatkupt, W G Johnson. Waardenburg syndrome and myelomeningocele in a family J Med Genet.1993 January; 30(1):83-84.
23. A P Read, V E Newton. Waardenburg syndrome.J Med Genet.1997 August; 34(8):656-665.
24. Filiz Hazan, A.Taylan Ozturk, Hamit Adibelli, et al. A novel missense mutation of the paired box 3 gene in a Turkish family with Waardenburg syndrome type 1Mol Vis.2013; 19: 196-202.
25. Sandy Leger, Xavier Balguerie, Alice Goldenberg,et al. Novel and recurrent non-truncating mutations of the MITF basic domain:genotypic and phenotypic variations in Waardenburg and Tietz syndromes. Eur J Hum Genet.2012; 20(5):584-587
26. N.M. Haddad, D. Ente, E. Chouery, N. Jalkh, et al. Molecular Study of Three Lebanese and Syrian Patients with Waardenburg Syndrome and Report of Novel Mutations in theEDNRB and MITF Genes.Mol Syndromol.2011 January; 1(4):169-175.
27. Friedman TB, Schultz JM, Ahmed ZM,et al. Usher syndrome:hearing loss with vision loss.Adv Otorhinolaryngol.2011;70:56-65.
28. Bonnet C, El-Amraoui A. Usher syndrome_(sensorineural deafness and retinitis pigmentosa): pathogenesis, molecular diagnosis and therapeutic approaches.Curr Opin Neurol. 2012;25(1):42-9.
29. Yan D, Liu XZ. Genetics and pathological mechanisms of Usher syndrome.J Hum Genet. 2010;55(6):327-35.
30. Earl TJ, Khan L, Hagau D,et al. The spectrum of aortic pathology in_alport syndrome:a case report and_review_of the literature.Am J Kidney Dis.2012;60(5):821-822.
31. Kruegel J, Rubel D, Gross O. Alport syndrome--insights from basic and clinical research.Nat Rev Nephrol.2013;9(3):170-178.
32. Yuanfeng Gao, Cuilan Li, Wenling Liu,et al. Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome. J Cardiovasc Dis Res.2012; 3(2):67-75.
33. Jae Suk Baek, Eun Jung Bae, Sang Yun Lee,et al. Jervell and Lange-Nielsen Syndrome: Novel Compound Heterozygous Mutations in the KCNQ1 in a Korean Family. J Korean Med Sci.2010; 25(10):1522-1525.
34. Renjian Zheng, Keith Thompson, Edmond Obeng-Gyimah, et al. Analysis of the interactions between the C-terminal cytoplasmic domains of KCNQ1 and KCNE1 channel subunits.Biochem J.2010; 428(1):75-84.
35. Maddalena Gigante, Marilena d'Altilia, Eustacchio Montemurno,et al. Branchio-Oto-Renal Syndrome (BOR) associated with focal glomerulosclerosis in a patient with a novel EYA1 splice site mutation.BMC Nephrol.2013; 14:60.
36. Amarilis Sanchez-Valle, Xueqing Wang, Lorraine Potocki, et al. HERV-Mediated Genomic Rearrangement of EYA1 in an Individual With Branchio-oto-renal Syndrome.Am J Med Genet A.2010; 152A(11):2854-2860.
37. Kaneto CM, Lima PS, Zanette DL,et al. COL1A1 and miR-29b show lower expression levels during osteoblast differentiation of bone marrow stromal cells from Osteogenesis Imperfecta patients.BMC Med Genet.2014;15(1):45
38. Stephen J, Shukla A, Dalal A,et al. Mutation spectrum of COL1A1 and COL1A2 genes in Indian patients with osteogenesis imperfecta.Am J Med Genet A.2014; 164(6):1482-9.
39. Izumi K, Konczal LL, Mitchell AL, Jones MC. Underlying genetic diagnosis of Pierre Robin sequence:retrospective chart review at two children's hospitals and a systematic literature review.J Pediatr.2012;160(4):645-650.
40. Li K, Thorne C. Adult presentation of.Stickler syndrome type Ⅲ.Clin Rheumatol. 2010;29(7):795-7.
41. Snead MP, McNinch AM, Poulson AV,et al. Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist.Eye (Lond).2011;25(11):1389-400.
42. Evans GR, Lloyd SK, Ramsden RT. Neurofibromatosis type 2.Adv Otorhinolaryngol. 2011;70:91-8.
43. Blakeley JO, Evans DG, Adler J,et al. Consensus recommendations for current treatments and accelerating clinical trials for patients with neurofibromatosis type 2.Am J Med Genet A. 2012 Jan;158A(1):24-41.
44. Lloyd SK, Evans DG. Neurofibromatosis type 2 (NF2):diagnosis and management.Handb Clin Neurol.2013:115:957-67.
45. Chang CC, Steinbacher DM. Treacher collins syndrome.Semin Plast Surg.2012;26(2):83-90.
46. Konstantinidou AE, Tasoulas J, Kallipolitis G,et al. Mandibulofacial dysostosis (Treacher-Collins syndrome) in the fetus:novel association with Pectus carinatum in a molecularly confirmed case and_review_of the fetal phenotype.Birth Defects Res A Clin Mol Teratol.2013;97(12):774-780.
47. Kadakia S, Helman SN, Badhey AK, et al. Treacher Collins Syndrome:The genetics of a craniofacial disease.Int J Pediatr Otorhinolaryngol.2014;78(6):893-898.
1. 迟放鲁,王璟,袁雅生,等.中耳手术中的面神经定位.中华耳鼻咽喉头颈外科杂志,2006,41(1)：5-8.
2. Raine CH,Hussain SS,Khan S,et al. Anomaly of the facial nerve and cochlear implantation. Ann Otol Rhinol Laryngol Suppl,1995,166:430-431.
3. Arnoldner C, Baumgartner WD, Gstoettner W,et al. Surgical considerations in cochlear implantation in children and adults:a review of 342 cases in Vienna. Acta Otolaryngol, 2005,125(3):228-234.
4. Song JJ, Park JH, Jang JH,et al. Facial nerve aberrations encountered during cochlear implantation. Acta Otolaryngol,2012,132(7):788-794.
5. Fayad JN, Wanna GB, Micheletto JN,et al. Facial nerve paralysis following cochlear implant surgery. Laryngoscope,2003,113(8):1344-1346.
6. 朱杭军,廖建春,王海清,等.鼓索神经颞骨部的解剖及临床应用.解剖与临床,2003,8(4)：201-202.
7. Jeon EJ, Jun B, Song JN,et al. Surgical and radiologic anatomy of a cochleostomy produced via posterior tympanotomy for cochlear implantation based on three-dimensional reconstructed temporal bone CT images. Surg Radiol Anat,2013 Jan 3.
8. Calli C, Pinar E, Oncel S,et al. Measurements of the facial recess anatomy:implications for sparing the facial nerve and chorda tympani during posterior tympanotomy. Ear Nose Throat J,2010,89(10):490-494.
9. 李健东,李娟,汪学勇,等.面神经减压术中鼓索解剖观察及临床意义.中国临床解剖学杂志,20]1,29(1)：7-9.
10. McManus LJ, Stringer MD, Dawes PJ. Iatrogenic injury of the chorda tympani:a systematic review. J Laryngol Otol,2012,126(1):8-14.
11. Guinand N, Just T, Stow NW,et al. Cutting the chorda tympani:not just a matter of taste. J Laryngol Otol,2010,124(9):999-1002.
12. Bielamowicz SA, Coker NJ, Jenkins HA, et al. Surgical dimensions of the facial recess in adults and children.Arch Otolaryngol Head Neck Surg,1988,114(5):534-537.
13.何利平,贺飞,李永新,等.人工耳蜗植入相关的解剖学研究.耳鼻咽喉头颈外科,2002,9(3)：168-170.
14. Su WY,Marion MS,Hinojosa R,et al.Anatomical measurements of the cochlear aqueduct,round window_membrane,round windowniche, and facial recess. Laryngoscope,1982,92(5):483-486.
15.张道行.人工耳蜗电极植入耳蜗入口的定位.临床耳鼻咽喉科杂志,2000,14(5)：195-196.
16.王明辉,张秋贵,张晓恒,等.经乳突-面隐窝径路人工耳蜗植入术解剖学研究.青岛大学医学院学报,2009,45(03)：267-268+271.
17.邹团明,郭梦和,张宏征,等.人工耳蜗植入术鼓阶入口定位的相关解剖研究.南方医科大学学报,2012,32(6)：904-907.
18. Trinh BT, Bergeron F, Ferron P. Long-term follow-up of cochlear implant users with ossified cochlea. J Otolaryngol,2000,29(5):279-284.
19. Hodges AV, Balkany TJ, Gomez-Marin O, et al.Speech recognition after implantation of the ossified cochlea. Am J Otol,1999,20(4):453-456.
20. Nadol JB Jr. Patterns of neural degeneration in the human cochlea and auditory nerve: implications for cochlear implantation. Otolaryngol Head Neck Surg,1997,117(3 Pt 1): 220-228.
21. Balkany T, Gantz BJ, Steenerson RL,et al. Systematic approach to electrode insertion in the ossified cochlea. Otolaryngol Head Neck Surg,1996,114(1):p.4-11.
22. Young NM, Hughes CA, Byrd SE, et al. Postmeningitic ossification in pediatric cochlear implantation. Otolaryngol Head Neck Surg,2000,122(2):183-188.
23. Berrettini S, Forli F, Neri E, et al. Scala vestibuli cochlear implantation in patients with partially ossified cochleas. J Laryngol Otol,2002,116(11):946-950.
24. Taibah K. The transmeatal approach:a new technique in cochlear and middle ear implants. Cochlear Implants Int,2009,10(4):218-228.
25. Postelmans JT, Tange RA, Stokroos RJ,et al. The suprameatal approach: a safe alternative surgical technique for cochlear implantation. Otol Neurotol,2010,31(2):196-203.
26. Ozturan O, Bauer CA, Miller CC 3rd,et al. Dimensions of the sinus tympani and its surgical access via a retrofacial approach. Ann Otol Rhinol Laryngol,1996,105(10):776-783.
[2]Morton CC,Nance WE.Newborn hearing screening-a silent revolution. N Engl J Med. 2006;354(20):2151-2164.
[3]第二次残疾人抽样调查办公室.全国第二次残疾人抽样调查主要数据手册.北京；华夏出版社,2007：2,38.
[4]王国建.耳聋基因诊断的临床实践.解放军军医进修学院博士论文,2008年
[5]胡浩,邬玲仟,梁德生,等.学语前性耳聋疾病相关基因的产前诊断.中华妇产科杂志,2005,40：591-594.
[6]韩明昱,楚严,卢彦平,等.孕期女性常见耳聋基因筛查与耳聋出生缺陷干预.中华耳科学杂志,2011,9(3)：289-295.
[7]骆为祥.少数民族人口分布及其变动分析.南方人口,2008,23(1)：42-50.
[8]Bayazit YA, Yilmaz M. An overview of hereditary hearing loss. ORL J Otorhinolaryngol Relat Spec.2006;68(2):57-63.
[9]《世界人类基因组与人权宣言》.联合国教科文组织第29届大会.1997年,巴黎.
[10]《世界医学协会赫尔辛基宣言》.第64届世界医学协会联合大会,福塔莱萨,巴西,2013年10月
[11]Miller, S.A., D.D. Dykes, and H.F. Polesky, A simple salting out procedure for extracting DNA from human nucleated cells. Nucl. Acids Res.,1988.16(3):p.1215.
[12]徐杰舜.中国民族关系发展大趋势论.学术探索.2011,10：55-63
[13]曹宗富,曹彦荣,马立广,等.中国人类遗传资源共享利用的标准化研究.遗传.2008,30(1)：51-58.
[14]Duman D,Mustafa Tekin. Autosomal recessive nonsyndromic deafness genes:a review. Front Biosci.2012,17:2213-2236.
[15]Zelante L, Gasparini P, Estivill X,et al. Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet.1997,6(9):1605-1609.
[16]Kelsell DP, Dunlop J, Stevens HP,et al. Connexin 26 mutations in hereditary nonsyndromic sensorineural deafness. Nature.1997,387(6628):80-83.
[17]Mhaske PV, Levit NA, Li L, et al. The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity. American Journal of Physiology:Cell Physiology.2013,304(12):1150-1158.
[18]de Zwart-Storm EA, van Geel M, Veysey E, et al. A novel missense mutation in GJB2, p.Tyr65His, causes severe Vohwinkel syndrome. Br J Dermatol.2011;164(1):197-199.
[19]Birkenhager R, Lublinghoff N, Prera E, et al. Autosomal dominant prelingual hearing loss with palmoplantar keratoderma syndrome:Variability in clinical expression from mutations of R75W and R75Q in the GJB2 gene. American Journal of Medical Genetics A.2010; 152(7):1798-1802.
[20]Guilford P, Ben Arab S, Blanchard S,et al. A non-syndrome form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat Genet.1994;6:24-28.
[21]Bruzzone R, White TW, Paul DL. Connections with connexins:the molecular basis of direct intercellular signaling. Eur J Biochem.1996;238(1):1-27.
[22]Nakagawa S, Maeda S, Tsukihara T. Structural and functional studies of gap junction channels.Current Opinion in Structural Biology.2010;20(4):423-430.
[23]Saez JC, Schalper KA, Retamal MA,et al. Cell membrane permeabilization via connexin hemichannels in living and dying cells. Experimental Cell Research.2010; 316(15): 2377-2389.
[24]Harris AL, Bevans CG. Exploring hemichannel permeability in vitro. Methods Mol Biol 2001;154:357-377.
[25]Mukherjee M, Phadke SR, Mittal B. Connexin 26 and autosomal recessive non-syndromic hearing loss. Indian J Hum Genet, 2003,9:40-50.
[26]Takada Y, Beyer LA, Swiderski DL,et al. Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy. Hear Res.2014;309:124-135.
[27]Cohen-Salmon M,Ott T,Michel V,et al.Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment andcell death. Curr Biol.2002;12(13):1106-1111.
[28]Wei Q, Huang H. Insights into the role of cell-cell junctions in physiology and disease. International Review of Cell and Molecular Biology.2013;306:187-221.
[29]Beltramello M, Piazza V, Bukauskas FF,et al. Impaired permeability to ins(1,4,5)p3 in a mutant connexin underlies recessive hereditary deafness. Nat Cell Biol.2005;7(1):63-69.
[30]Kikuchi T, Kimura RS, Paul DL,et al. Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis. Anat Embryol (Berl).1995;191(2):101-118.
[31]Lefebvre PP, Van De Water TR. Connexins, hearing and deafness:clinical aspects of mutations in the connexin 26 gene. Brain Res Brain Res Rev.2000;32(1):159-162.
[32]Kikuchi T, Kimura RS, Paul DL,et al. Gap junction systems in the mammalian cochlea. Brain Res Brain Res Rev.2000;32(1):163-166.
[33]Van Laer L, Cryns K, Smith RJ,et al. Nonsyndromic hearing loss. Ear Hear.2003;24(4):275-88.
[34]Wangemann P.K(+) cycling and its regulation in the cochlea and the vestibular labyrinth. Audiol Neurootol.2002;7(4):199-205.
[35]Bitner-Glindzicz M. Hereditary deafness and phenotyping in humans.Br Med Bull,2002, 63(1):73-94.
[36]Oguchi T, Ohtsuka A, Hashimoto S, et al. Clinical features of patients with GJB2 (connexin 26) mutations:severity of hearing loss is correlated with genotypes and protein expression patterns. J Hum Genet.2005;50(2):76-83.
[37]Ballana E,Ventayol M,Rabionet R,Gasparini P, Estivill X.Connexins and deafness homepage.http://davinci.crg.es/deafness/Accessed 5 March 2014.
[38]Hilgert N, Smith RJH, van Camp G. Forty-six genes causing nonsyndromic hearing impairment:which ones should be analyzed in DNA diagnostics? Mutation Research.2009;681(2-3):189-196.
[39]Van Camp G, Willems PJ, Smith RJ.Nonsyndromic hearing impairment:unparalleled heterogeneity. Am J Hum Genet.1997;60(4):758-764.
[40]Gasparini P, Rabionet R, Barbujani G, et al. High carrier frequency of the c.35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 c.35delG. Eur J Hum Genet.2000; 8(1):19-23.
[41]Park HJ, Hahn SH, Chun YM, et al.Connexin26 mutations associated with nonsyndromic hearing loss. Laryngoscope.2000;110(9):1535-1538.
[42]Kudo T, Ikeda K, Kure S, et al.Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population. Am J Med Genet.2000;90(2): 141-145.
[43]Liu Y, Ke X, Qi Y,et al. Connexin26 gene (GJB2):prevalence of mutations in the Chinese population. J Hum Genet.2002;47(12):688-690.
[44]Pu Dai, Fei Yu, Bing Han,et al. GJB2 mutation spectrum in 2063 Chinese patients with nonsyndromic hearing impairment. J Transl Med.2009; 7:26.
[45]Chen Y, Tudi M, Sun J,et al. Genetic mutations in non-syndromic deafness patients of Uyghur and Han Chinese ethnicities in Xinjiang, China:a comparative study. J Transl Med.2011;9:154.
[46]Chen K, Zong L, Liu M,et al. Developing regional genetic counseling for southern Chinese with nonsyndromic hearing impairment:a unique mutational spectrum. J Transl Med.2014;12:64.
[47]Dai P, Yu F, Han B, et al. The prevalence of the c.235delC GJB2 Mutation in a Chinese Deaf Population. Genet Med.2007; 9(5):283-289.
[48]于飞,戴朴,韩东一.GJB2基因突变及语前遗传性非综合征性耳聋.国外医学耳鼻咽喉科学分册,2005,29：359-361.
[49]Ohtsuka A, Yuge I, Kimura S,et al. GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. Hum Genet. 2003;112(4):329-333.
[50]Yan D, Park HJ, Ouyang XM,et al. Evidence of a founder effect for the c.235delC mutation of GJB2 (connexin 26) in east Asians. Hum Genet.2003;114(1):44-50.
[51]Van Laer L, Coucke P, Mueller RF, et al. A common founder for the c.35delG GJB2 gene mut ation in connexin 26 hearing impairent. J Med Genet.2001,38(8):515-518.
[52]Jun AI,McGuirt WT,Hinojosa R,et al. Temporal bone histopathology in connexin 26-related hearing loss. Laryngoscope.2000,110 (2 Pt 1):269-275.
[53]Chan DK, Schrijver 1, Chang KW.Diagnostic yield in the workup of congenital sensorineural hearing loss is dependent on patient ethnicity. Otol Neurotol.2011;32(1): 81-87.
[54]Tsukada K, Nishio S, Usami S.A large cohort study of GJB2 mutations in Japanese hearing loss patients. Clin Genet.2010;78(5):464-470.
[55]Han SH, Park HJ, Kang EJ, et al. Carrier frequency of GJB2 (connexin-26) mutations causing nherited deafness n the Korean population. J Hum Genet.2008;53(11-12):1022-1028.
[56]Kim SY, Lee BY, Lim JH,et al.Determination of the carrier frequencies of selected GJB2 mutations in the Korean population. Int J Audiol.2011;50(10):694-698.
[57]Kelley PM, Harris DJ, Comer BC,et al. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet.1998;62(4):792-799.
[58]Chan DK, Schrijver I, Chang KW.Connexin-26-associated deafness:phenotypic variability and progression of hearing loss. Genet Med.2010; 12(3):174-181.
[59]Xiao ZA, Xie DH. GJB2 (Cx26) gene mutations in Chinese patients with congenital sensorineural deafness and a report of one novel mutation. Chin Med J (Engl).2004; 117(12):1797-1801.
[60]贺定华,冯永,夏昆,等.GJB2基因在遗传性聋中的检测.听力学及言语疾病杂志,2005,13(5)：301-303.
[61]Palmada M, Schmalisch K, Bohmer C, et al.Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. Neurobiol Dis.2006;22(1): 112-118.
[62]Huculak C,Bruyere H,Nelson TN,et al.V37I connexin 26 allele in patients with sensorineural hearing loss:evidence of its pathogenicity. Am J Med Genet A.2006;140(22): 2394-2400.
[63]Schrijver I, Chang KW.Two patients with the V37I/c.235delC genotype:are radiographic cochlear anomalies part of the phenotype? Int J Pediatr Otorhinolaryngol2006;70(12): 2109-2113.
[64]Lei Li,Jingrong Lu, Zheng Tao,et al. The p.V37I Exclusive Genotype Of GJB2:A Genetic Risk-Indicator of Postnatal Permanent Childhood Hearing Impairment.PLoS One.2012; 7(5):e36621.
[65]Wilcox SA,Saunders K,Osborn AH,et al.High frequency hearing loss correlated with mutations in the GJB2 gene. Hum Genet.2000;106(4):399-405.
[66]Bruzzone R, Veronesi V, Gomes D,et al.Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett.2003.533(1-3): 79-88.
[67]Jara O, Acuna R, Garcia IE, et al.Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function. Mol Biol Cell.2012;23(17):3299-3311.
[68]Wattanasirichaigoon D,Limwongse C,Jariengprasert C,et al. High prevalence of V37I genetic variant in the connexin-26 (GJB2) gene among non-syndromic hearing-impaired and control Thai individuals. Clin Genet.2004;66(5):452-460.
[69]Abe S, Usami S, Shinkawa H,et al. Prevalent connexin 26 gene (GJB2) mutations in Japanese. J Med Genet.2000;37(1):41-43.
[70]Gualandi F, Ravan iA, Berto A, et al. Exploring the clinical and epidemiological complexity of GJB2-linked deafness. Am J Med Genet.2002;112(1):38-45.
[71]Snoeckx RL, Huygen PL, Feldmann D,et al.GJB2 mutations and degree of hearing loss:a multi-center study. Am J Hum Genet.2005;77(6):945-957.
[72]Cryns K, Orzan E, Murgia A, et al.A genotype-phenotype correlation for GJB2(connexin 26) deafness. J Med Genet.2004;41(3):147-154.
[73]Feng Xin, Yongyi Yuan, Xiaoming Deng,et al. Genetic mutations in nonsyndromic deafness patients of Chinese minority and han ethnicities in Yunnan, China. J Transl Med.2013; 11:312.Published online Dec 17,2013.
[74]yubin Ji, dongyi Han, Ian Lan,et al. Molecular epidemiological analysis of mitochondrial DNA 12SrRNA A1555G,GJB2, and SLC26A4 mutations in sporadic outpatients with nonsyndromic sensorineural hearing loss in China. Acta Otolaryngol.2011; 131(2):124-129.
[75]Yongyi Yuan,Yiwen You, Deliang Huang,et al.Comprehensive molecular etiology analysis of nonsyndromic hearing impairment from typical areas in China.J Transl Med.2009;7:79.
[76]马虎成.《撒尔塔：一个曾经被忽略的民族名称》(上)、(下).《西北民族研究》1992(2),55-64.
[77]Nina Danilenko, Elena Merkulava, Marina Siniauskaya,et al. Spectrum of Genetic Changes in Patients with Non-Syndromic Hearing Impairment and Extremely High Carrier Frequency of c.35delG GJB2 Mutation in Belarus. PLoS One.2012; 7(5):e36354.
[78]Downs MP. Universal newborn hearing screening-the Colorado story. Int J Pediatr Otorhinolaryngol.1995;14:257-259.
[79]Mehl AL, Thomson V. The Colorado newborn hearing screening project,1992-1999:on the threshold of effective population-based universal newborn hearing screening. Pediatrics.2002;14:E7.
[80]Tom Walsh,Sarah B. Pierce,Danielle R. Lenz,et al. Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51.Am J Hum Genet.2010,87(l):101-109.
[81]郭玉芬,关静,徐百成,等.甘肃省盲聋哑学校283名聋哑学生的病因分析.中华耳科学杂 志;,2006,4(1):30-33.
[82]Morton NE. Genetic epidemiogy of hearing impairment. Ann NY Acad Sci.1991;14:16-31.
[83]A. Eliot Shearer and Richard J.H. Genetics:advances in genetic testing for deafness.PMC, Curr Opin Pediatr.2012,24(6):679-686.
[84]Nance WE. The genetics of deafness. Ment Retard Dev Disabil Res Rev.2003,8:109-119.
[85]Bamiou DE, Phelps P, Sirimanna T. Temporal bone computed tomography findings in bilateral sensorineural hearing loss. Arch Dis Child.2000;82(3):257-260.
[86]Mafong DD, Shin EJ, Lalwani AK. Use of laboratory evaluation and radiologic imaging in the diagnostic evaluation of children with sensorineural hearing loss.Laryngoscope.2002;112(1):1-7.
[87]Wu CC, Chen YS, Chen PJ, et al. Common clinical features of children with enlarged vestibular aqueduct and Mondini dysplasia. Laryngoscope.2005;115(1):132-137.
[88]Antonelli P,Varela A,Mancuso A.Diagnostic yield of high-resolution computed tomography for pediatric sensorineural hearing loss. Laryngoscope.1999; 109:1642-1647.
[89]Valvassori G, Clemis J. The large vestibular aqueduct syndrome. Laryngoscope.1978;88:273-278.
[90]Madden C, Halsted M, Meinzen-Derr J,et al. The influence of mutations in the SLC26A4 gene on the temporal bone in a population with enlarged vestibular aqueduct. Arch Otolaryngol Head Neck Surg.2007; 133(2):162-168.
[91]Phelps PD, Coffey RA, Trembath RC,et al. Radiological malformations of the ear in Pendred syndrome. Clin Radiol.1998;53:268-273.
[92]Chen A, Francis M, Ni L, et al.:Phenotypic manifestations of branchio-oto-renal syndrome. Am J Med Genet 1995;58:365-370.
[93]Madden C, Halsted MJ, Hopkin RJ, et al.Temporal bone abnormalities associated with hearing loss in Waardenburg syndrome. Laryngoscope.2003;113:2035-2041.
[94]Everett LA, Glaser B, Beck JC,et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet.1997;17:411-422.
[95]Li XC, Everett LA, Lalwani AK,et al. A mutation in PDS causes non-syndromic recessive deafness. Nat Genet.1998; 18:215-217.
[96]杨伟炎,张素珍,赵承君,等.95例大前庭水管综合征的临床分析.中华耳鼻咽喉科杂志，2003：38：191一194.
[97]Campbell C, Cucci RA, Prasad S,et al. Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutation and possible genotype-phenotype correlations. Hum Mutat.2001;14:404-411.
[98]Azaiez H, Yang T, Prasad S,et al. Genotype-phenotype correlations for SLC26A4-related deafness. Hum Genet.2007;122(5):451-457.
[99]Scott D, Wang R, Kreman T,et al.Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and nonsyndromic hearing loss (DFNB4). Hum Mol Genet.2000;9:1709-1715.
[100]Saier MH J,Zhai Yr. A web-based program (WHAT) for the simultaneous prediction of hydropathy, amphipathicity, secondary structure and transmembrane topology for a single protein sequence. J Mol Microbiol Biotechnol.2001;3(4):501-502.
[101]Lorraine A. Everett, Hakim Morsli, Doris K. Wu,et al. Expression pattern of the mouse ortholog of the Pendred's syndrome gene (Pds) suggests a key role for pendrin in the inner ear. Proc Natl Acad Sci U S A.1999; 96(17):9727-9732.
[102]Yoshino T, Sato E, Nakashima T, Teranishi M,et al. Distribution of pendrin in the organ of corti of mice observed by electron immunomicroscopy. Eur Arch Otorhinolaryngol.2006;263:699-704.
[103]Wangemann P, Nakaya K, Wu T,et al. Loss of cochlear HCO3-secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model. Am J Physiol Renal Physiol.2007;292(5):F1345-53.
[104]Everett LA, Belyantseva IA, Noben-Trauth K, et al.Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. Hum Mol Genet.2001;10:153-161.
[105]Scott DA, Wang R, Kreman TM,et al. The Pendred syndrome gene encodes a chloride-iodide transport protein. Nat Genet.1999;21(4):440-443.
[106]Park HJ, Shaukat S, Liu XZ,et al. Origins and frequencies of SLC26A4 (PDS) mutations in East and South Asians:glogal implications for the epidemiology of deafness. J Med Genet.2003;40:242-248.
[107]Van Hauwe P, Everett LA, Coucke P,et al. Two frequent missense mutations in pendred syndrome. Hum Mol Genet.1998;7:1099-1104.
[108]Coyle B, Reardon W, Herbrick JA,et al. Molecular analysis of the PDS gene in Pendred syndrome. Hum Mol Genet.1998;7:1105-1112.
[109]Alejandra Pera,Silvia Dossena,Simona Rodighiero,et al. Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA. Proc Natl Acad Sci USA.2008; 105(47):18608-18613.
[110]Tsukamoto K, Suzuki H, Harada D,et al. Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct:a unique spectrum of mutations in Japanese. Eur J Hum Genet.2003; 14:916-922.
[111 Wang QJ, Zhao YL, Rao SQ, et al. A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China. Clin Genet.2007;72:245-254.
[112]Wu CC, Yeh TH, Chen PJ, et al. Prevalent SLC26A4 mutations in patients with enlarged vestibular aqueduct and/or Mondini dysplasia:a unique spectrum of mutations in Taiwan, including a frequent founder mutation. Laryngoscope.2005; 115:1060-1064.
[113]Hu X, Liang F, Zhao M,et al. Mutational analysis of the SLC26A4 gene in Chinese sporadic nonsyndromic hearing-impaired children. Int J Pediatr Otorhinolaryngol.2012;76:1474-1480.
[114]Mark van der Giezen, Jorge Tovar.Degenerate mitochondria.EMBO Rep.2005,6(6): 525-530.
[115]Patrick Francis Chinnery,Gavin Hudson. Mitochondrial genetics. Br Med Bull. Jun 2013,106(1):135-159.
[116]Schaefer AM,Taylor RW,Turnbull DM,et al.The epidemiology of mitochondrial disorders - past, present and future. Biochim Biophys Acta.2004,1659:115-120.
[117]Andrews RM, Kubacka I, Chinnery PF, et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet.1999,23:147.
[118]Temperley R, Richter R, Dennerlein S, et al. Hungry codons promote frameshifting in human mitochondrial ribosomes. Science.2010,327:301.
[119]Sutovsky P. Ubiquitin-dependent proteolysis in mammalian spermatogenesis, fertilization, and sperm quality control:killingthree birds with one stone. Microsc Res Tech.2003,61(1):88-102.
[120]Birky CW, Jr The inheritance of genes in mitochondria and chloroplasts:laws, mechanisms, and models. Annu Rev Genet.2001,35:125-148.
[121]Jochen Schacht, Andra E. Talaska, Leonard P. Rybak. Cisplatin and Aminoglycoside Antibiotics:Hearing Loss and Its Prevention.Anat Rec (Hoboken).2012,295(11):1837-1850.
[122]丁大连,金晓杰,赵纪余.卡那霉素在耳蜗毛细胞中的积聚部位.中华耳鼻咽喉科杂志,1997,32：348-349.
[123]Swan SK. Aminoglycoside nephrotoxicity. Semin Nephrol.1997,17(1):27-33.
[124]Jing Xie, Andra E. Talaska, Jochen Schacht. New developments in aminoglycoside therapy and ototoxicity.Hear Res.2011,281(1-2):28-37.
[125]Prezant TR,Aga Pian JV,Bohlman MC,et al. mitochondria ribosomal RNA mutation associatedwithbothantibiotie - indueedandnon syndromie dealness. Nat Genet. 1993,4(3):289 -294.
[126]De Rijk P, De Wachter R. RnaViz, a program for the visualisation of RNA secondary structure. Nucleic Acids Res.1997,25(22):4679-4684.
[127]Lu JX, Li ZY, Zhu Y,et al. Mitochondrial 12S rRNA variants in 1642 Han Chinese pediatricsubjects with aminoglycoside-induced and nonsyndromic hearing loss. Mitochondrion.2010,10(4):380-390.
[128]Hutchin T.Sensorineural hearing loss and the 1555G mitochondrial DNA mutation. Acta Otolaryngol.1999,119(1):48-52.
[129]Ouyang XM. Yan D. YH Dai P, et al. The genetic bases for non-syndromic hearing loss among Chinese. J Hum Genet.2009,54:131-140.
[130]Ying-Chang Lu, Chen-Chi Wu, Ting-Hua Yang, et al. Differences in the Pathogenicity of the p.H723R Mutation of the Common Deafness-Associated SLC26A4 Gene in Humans and Mice.PLoS One.2013; 8(6):e64906.
[131]Yang JJ, Tsai CC, Hsu HM, et al. Hearing loss associated with enlarged vestibular aqueduct and Mondini dysplasia is caused by splice-site mutation in the PDS gene. Hear Res.2005;199:22-30.
[132]Park HJ, Lee SJ, Jin HS, et al. Genetic basis of hearing loss associated with enlarged vestibular aqueducts in Koreans. Clin Genet.2005;67(2):160-165.
[133]穆豪放,陈峰,熊新,等.中国青海藏族、汉族mtDNA控制区遗传多态性.法医学杂志.2008,24(6)：417-422.
[134]to T, Choi BY, King KA, Zalewski CK,et al.SLC26A4 genotypes and phenotypes associated with enlargement of the vestibular aqueduct. Cell Physiol Biochem.2011;28(3):545-552.
[135]Boston M, Halsted M, Meinzen-Derr J,et al. The large vestibular aqueduct: a new definition based on audiologic and computed tomography correlation. Otolaryngol Head Neck Surg.2007;136(6):972-977.
[136]Pryor SP, Madeo AC, Reynolds JC,et al. SLC26A4/PDS genotype-phenotype correlation in hearing oss with enlargement of the vestibular aqueduct(EVA):evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities. J Med Genet.2005 Feb;42(2):159-65.
[137]Hutchin TP, Thompson KR, Parker M,et al. Prevalence of mitochondrial DNA mutations in childhood/congenital onset non-syndromal sensorineural hearing impairment. J Med Genet.2001,38(4):229-231.
[138]VALERIA GUARAN, LAURA ASTOLFI, ALESSANDRO CASTIGLIONE,et al. Association between idiopathic hearing loss and mitochondrial DNA mutations:A study on 169 hearing-impaired subjects. Int J Mol Med.2013,32(4):785-794.
[139]Richard J, Vivero,Xiaomei Ouyang, Denise Yan,et al. Mitochondrial DNA Mutation Screening in an Ethnically Diverse Nonsyndromic Deafness Cohort. Genet Test Mol Biomarkers.2012,16(9):1146-1148.
[140]Tessa A, Giannotti A, Tieri L, et al. Maternally inherited deafness associated with a T1095C mutation in the mDNA. Eur J Hum Genet,2002,9(2):147-149.
[141]Usami SI, Abe S, Akita J, et al. Prevalence of mitochondrial gene mutations among hearing impaired patients.J Med Genet.2000,37(1):38-40.
[142]Guan MX. Mitochondrial 12S rRNA mutations associated with aminoglycoside ototoxicity.Mitochondrion.2011,11(2):237-245.
[143]谢小冬,陕雪梅.回族起源的DNA证据.回族研究.2002,(3)：75-78.
[144]Yao YG, Kong QP, Wang CY,et al. Different matrilineal contributions to genetic structure of ethnic groups in the silk road region in china. Mol Biol Evol.2004,21(12):2265-2280.
[145]Guan MX, Yan Q, Li X, et al. Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deaf-ness-associated mitochondrial 12S ribosomal RNA mutations. Am J Hum Genet.2006,79:291-302.
[146]龚莎莎,郑静,张婷,等.氨基糖苷类抗生素耳毒性相关的线粒体DNA突变.国际遗传学杂志.2011,34(4)：202-212.
[147]管敏鑫,赵立东.与氨基糖菅类抗生素耳毒性相关的线粒体12SrRNA突变的流行病学特征,中华耳科学杂志.2006,4(2)：98-105.
[148]Fischel-Ghodsian N, Prezant TR, Chaltraw WE,et al. Mitochondrial gene mutation is a significant predisposing factor in aminoglycoside ototoxicity. Am J Otolaryngol. 1997,18(3):173-178.
[149]Zhao H, Young WY, Yan Q, et al. Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with amino-glycoside-induced and non-syndromic hearing loss. Nucleic Acids Res.2005,33:1132-1139.
[150]X Estivill, N Govea, E Barcelo,et al. Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides. Am J Hum Genet.1998,62(1):27-35.
[151]Fraser GR. Association of congenital deafness with goiter (Pendred's syndrome):a study of 207 families. Ann Hum Genet.1965; 14:201-249.
[152]Stinckens C, Huygen PL, Joosten FB,et al. Fluctuant, progressive hearing loss associated with Meniere like vertigo in three patients with the Pendred syndrome. Int J Pediatr Otorhinolaryngol.2001;14:207-215.
[153]Cremers CW, Admiraal RJ, Huygen PL,et al. Progressive hearing loss, hypoplasia of the cochlea and widened vestibular aqueducts are very common features in Pendred's syndrome. Int J Pediatr Otorhinolaryngol.1998;14:113-123.
[154]Xing M, Tokumaru Y, Wu G,et al. Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis. Cancer Res.2003;63(9):2312-2315.
[155]Jackler RK, de la Cruz A.The large vestibular aqueduct syndrome. Laryngoscope. 1989;14:1238-1243.
[156]Arcand P, Desrosiers M, Dube J,et al. The large vestibular aqueduct syndrome and seisorineural hearing loss in the pediatric population. J Otolaryngol.1991;14:247-250.
[157]Okumura T, Takahashi H, Honjo I, et al. Sensorineural hearing loss in patients with large vestibular aqueduct. Laryngoscope.1995;14:289-294.
[158]Mamikodlu B, Bentz B, Wiet RJ. Large vestibular aqueduct syndrome presenting with mixed hearing loss and an intact mobile ossicular chain. Otorhinolaryngol Nova.2000; 10:204-206.
[159]Saumil N. Merchant, Hideko H. Nakajima, Christopher Halpin,et al. Clinical Investigation and Mechanism of Air-Bone Gaps in Large Vestibular Aqueduct Syndrome. Ann Otol Rhinol Laryngol.2007; 116(7):532-541.
[160]Saumil N. Merchant, John J. Rosowski.Conductive Hearing Loss Caused by Third-Window Lesions of the Inner Ear. Otol Neurotol.2008; 29(3):282-289.
[161]David N. Cooper,Michael Krawczak, Constantin Polychronakos,et al. Where genotype is not predictive of phenotype:towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet.2013; 132:1077-1130.
[162]Lu J, Qian Y, Li Z, et al. Mitochondrial haplotypes may modulate the phenotypic manifestation of the deafness-associated 2S rRNA 555A>G mutation. Mitochondrion.2010,10:69-81.
[163]Reid FM, Vernham GA, Jacobs HT. A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum Mutat.1994,3:243-247.
[164]Zhao H, Li RH,Wang QJ,et al. Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family. Am J Hum Genet.2004,74(l):139-152.
[165]Rodriguez-Ballesteros M, Olarte M, Aguirre LA,et al. Molecular and clinical characterisation of three Spanish families with maternally inherited non-syndromic hearing loss caused by the 1494C>T mutation in the mitochondrial 12S rRNA gene. J Med Genet.2006,43(11e54.
[166]Chen J, Yang L, Yang A,et al.Maternally inherited aminoglycoside-induced and nonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees. Gene.2007,401(1-2):4-11.
[167]Nadol JB Jr. Hearing loss. N Engl J Med.1993;329(15):1092-1102.
[168]Steel KP. Science, medicine, and the future:New interventions in hearing impairment. BMJ,2000,320(7235):622-625.
[169]Chatterjee A,Jalvi R, Pandey N,Rangasayee R,et al. A novel locus DFNA59 for autosomal dominant nonsyndromic hearing loss maps at chromosome 11p14.2-q12.3. Hum Genet.2009;124(6):669-675.
[170]Leon PE, Raventos H, Lynch E,et al.The gene for an inherited form of deafness maps to chromosome 5q31. Proc Natl Acad Sci U S A.1992;89(11):5181-5184.
[171]Cheng J,Zhu Y, He S,et al.Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64. Am J Hum Genet.2011,89(1):56-66.
[172]Van Camp G, Smith R J H. Hereditary hearing loss homepage.World Wide Web URL: http://dnalab-www.uia.ac.be/dnalab/hhh/,Last updated:April 29,2014.
[173]Manolis EN, Yandavi N, Nadol JB, et al.A gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12-13.Hum Molec Genet.1996;5(7):1047-1050.
[174]Robertson NG,Lu L,Heller S,et al.Mutations in a novel cochlear gene cause DFNA9,a human nonsyndromic deafness with vestibular dysfun ction. Nat Genet.1998;20(3):299-303.
[175]Fransen E, Van Camp G. The COCH gene:a frequent cause of hearing impairment and vestibular dysfunction? Br J Audio,1999,33(5):297-302.
[176]Robertson NG, Skvorak AB, Yin Y, et al. Mapping and characterization of a novel cochlear gene in human and in mouse:a positional candidate gene for a deafness disorder, DFNA9. Genomics.1997;46(3):345-354.
[177]Robertson NG, Resendes BL, Lin JS,et al.Inner ear localization of mRNA and protein products of COCH, mutated in the sensorineural deafness and vestibular disorder, DFNA9. Hum Mol Genet.2001;10(22):2493-2500.
[178]Khetarpal U, Schuknecht HF, Gacek RR,et al. Autosomal dominant sensorineural hearing loss. Pedigrees, audiologic findings, and temporal bone findings in two kindreds. Arch Otolaryngol Head Neck Surg.1991; 117(9):1032-1042.
[179]kezono T, Omori A, Ichinose S, et al. Identification of the protein product of the Coch gene (hereditary deafness gene) as the major component of bovine inner ear protein. Biochim Biophys Acta,2001,1535(3):258-265.
[180]Robertson NG, Hamaker SA, Patriub V, et al. Subcellular localisation, secretion, and post-translational processing of normal Cochlin, and of mutants causing the sensorineural deafness and vestibular disorder, DFNA9. J Med Genet,2003,40(7):479-486.
[181]Makishima T, Rodriguez CI, Robertson NG, et al. Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder. Hum Genet,2005,118(1):29-34.
[182]Merchant SN, Linthicum FH, Nadol JB Jr. Histopathology of the inner ear in DFNA9. Adv Otorhinolaryngol,2000,56:212-217.
[183]Khetarpal U. Autosomal dominant sensorineural hearing loss. Further temporal bone findings. Arch Otolaryngol Head Neck Surg.1993,119(1):106-108.
[184]Bom SJ, De Leenheer EM, Lemaire FX,et al. Speech recognition scores related to age and degree of hearing impairment in DFNA2/KCNQ4 and DF-NA9/COCH. Arch Otolaryngol Head Neck Surg.2001; 127(9):1045-1048.
[185]Verhagen WIM, Bom SJH, Fransen E, et al. Hereditary cochleovestibular dysfunction due to a COCH gene mutation (DFNA9):a follow-up study of a family. Clin Otolaryngol, 2001,26(6):477-483.
[186]De Kok YJM, Bom SJH, Brunt TM, et al. A Pro51 Ser mutation in the COCH gene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects. Hum Molec Genet,1999,8(2):361-366.
[187]Fransen E, Verstreken M, Verhagen WIM, et al. High prevalence of symptoms of Meniere's disease in three families with a mutation in the COCH gene. Hum Mol Genet, 1999,8(8):1425-1429.
[188]Kamarinos M, McJill J, Lynch M, et al. Identification of a novel COCH mutation, I109N, highlights the similar clinical features observed in DFNA9 families. Hum Mutat, 2001,17(4):351.
[189]Fransen E, Verstreken M, Bom SJH, et al. A common ancestor for COCH related cochleovestibular (DFNA9) patients in Belgium and The Netherlands bearing the P51S mutation. J Med Genet,2001,38(1):61-64.
[190]Usami S, Takahashi K, Yuge I, et al. Mutations in the COCH gene are a frequent cause of autosomal dominant progressive cochleo-vestibular dysfunction, but not of Meniere's disease. Eur J Hum Genet,2003,11(10):744-748.
[191]Nagy I, Horvath M, Trexler M, et al. A novel COCH mutation, V104del, impairs folding of the LCCL domain of cochlin and causes progressive hearing loss. J Med Genet,2004,41: e9.
[192]Street VA, Kallman JC, Robertson NG, et al. A novel DFNA9 mutation in the vWFA2 domain of COCH alters a conserved cysteine residue and intrachain disulfide bond formation resulting in progressive hearing loss and site-specific vestibular and central oculomotor dysfunction. Am J Med Genet A,2005,139(2):86-95.
[193]Collin RWJ, Pauw RJ, Schoots J, et al. Identification of a novel COCH mutation, G87W, causing autosomal dominant hearing impairment (DFNA9). Am J Med Genet A,2006,140 (16):1791-1794.
[194]Chen DY, Chai YC, Yang T,et al. Clinical characterization of a novel COCH mutation G87V in a Chinese DFNA9 family. Int J Pediatr Otorhinolaryngol.2013;77(10):1711-1715.
[195]Pauw RJ, Huygen PL, Colditz GM,et al. Phenotype analysis of an Australian DFNA9 family with the 1109N COCH mutation. Ann Otol Rhinol Laryngol.2011;120(6):414-21.
[196]Hildebrand MS, Gandolfo L, Shearer AE,et al. A novel mutation in COCH-implications for genotype-phenotype correlations n DFNA9 hearing oss. Laryngoscope.2010; 120(12):2489-2493.
[197]Sun Q, Yang SZ, Kang DY,et al.Mutation screening of the COCH gene in familial and sporadic patients with late onset nonsyndromic sensorineural hearing loss among Chinese population. Zhonghua Yi Xue Za Zhi.2007;87(44):3107-3110.
[198]Cho HJ, Park HJ, Trexler M,et al. A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain. J Mol Med (Berl).2012;90(11):1321-1331.
[199]Gao J, Xue J, Chen L,et al. Whole exome sequencing identifies a novel DFNA9 mutation, C162Y. Clin Genet.2013;83(5):477-481.
[200]刘万清,博邵春,贺林.解码生命[M].北京：科学出版社,2000.
[201]孙悍军.常染色体显性遗传非综合征型耳聋基因定位克隆.解放军军医进修学院博十论文，2005年.
[202]Robertson NG, Cremers CW, Huygen PL,et al. Cochlin immunostaining of inner ear pathologic deposits and proteomic analysis in DFNA9 deafness and vestibular dysfunction. Hum Mol Genet.2006;15(7):1071-1085.
[203]Yuan HJ, Han DY, Sun Q,et al. Novel mutations in the vWFA2 domain of COCH in two Chinese DFNA9 families. Clin Genet.2008;73(4):391-394.
[204]Kommareddi PK, Nair TS, Raphael Y, et al. Cochlin isoforms and their interaction with CTL2 (SLC44A2) in the inner ear. J Assoc Res Otolaryngol 2007,8:435-446.
[205]Yao J, Py BF, Zhu H, Bao J, Yuan J. Role of protein misfolding in DFNA9 hearing loss. J Biol Chem 2010;285:14909-14919.
[206]Verstreken M, Declau F, Wuyts F L,et al. Hereditary otovestibular dysfunction and Meniere's disease in a large Bel-gian family is caused by a missense mutation in the COCH gene. Otology & Neurotology,2001,22 (6):874-881.
[207]Kemperman M H, De Leenheer M R, Huygen P L.et al. Audiometric, vestibular, and genetic aspects of a DFNA9 family with a G88E COCH Mutation. Otology & Neurotology,2005,26 (5):926-933.
[208]Committee on Hearing and Equilibrium.Guidelines for the diagnosis and evaluation of therapy in Meniere's disease[J].Otolaryngol Head Neck Surg,1995,113:181.
[209]Morrison AW. On genetic and environmental factors in Meniere's disease. Am. J. Otol.1994;15(1):35-39.
[210]Morrison AW, Bailey ME, Morrison GA.Familial Meniere's disease:clinical and genetic aspects. J Laryngol Otol.2009;123(1):29-37.
[211]孙燕,刘博,戴海江,等.梅尼埃病患者COCH(?)基因第4和5外显子突变研究[J].中华医学杂志,2005,85(5)：345-347.
[212]Irene Gazquez,Jose A Lopez-Escamez. Genetics of Recurrent Vertigo and Vestibular Disorders. Curr Genomics.2011; 12(6):443-450.
[213]Ali M. Waryah, Zubair M. Ahmed, et al.Molecular and Clinical Studies of X-linked Deafness Among Pakistani Families.J Hum Genet. J Hum Genet.2011;56(7):534-540.
[214]Zina ZB, Masmoudi S, Ayadi H, et al. From DFNB2 to Usher syndrome:variable expressivity of the same disease. Am. J. Med. Genet,2001,101(2):181-183.
[215]Baldwin CT, Weiss S, Farrer LA, et al. Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle Eastern Druze population. Hum. Mol.Genet.1995,4(9):1637-1642.
1. Nadol JB Jr. Hearing loss. N Engl J Med.1993;329(15):1092-1102.
2. Steel KP. Science, medicine, and the future:New interventions in hearing impairment. BMJ, 2000,320(7235):622-625.
3. Van Camp G, Willems PJ, Smith RJ.Nonsyndromic hearing impairment:unparalleled heterogeneity. Am J Hum Genet.1997;60(4):758-764.
4. Chatterjee A,Jalvi R, Pandey N,Rangasayee R,et al. A novel locus DFNA59 for autosomal dominant nonsyndromic hearing loss maps at chromosome 11p14.2-q12.3. Hum Genet.2009;124(6):669-675.
5. Gorlin RJ, Toriello HV, Cohen MM. Hereditary Hearing Loss and its Syndromes. Oxford University Press; New York:1995. pp.3-4.
6. Cranefield PF, Federn W. Paulus Zacchias on mental deficiency and on deafness. Bull N Y Acad ed.170;46:3-21.
7. Dow GS, Poynter CI. The Dar family. Eugen News.1930;15:128-130.
8. Van Camp G, Smith RJH. Hereditary Hearing Loss Homepage.2010 http://hereditaryhearingloss.org. Update:1.10.2010.
9. Leon PE, Raventos H, Lynch E, Morrow J, King MC. The gene for an inherited form of deafness maps to chromosome 5q31. Proc Natl Acad Sci U S A.1992;89:5181-5184.
10. Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, King MC. Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science.1997;278:1315-1318.
11. Guilford P, Ben Arab S, Blanchard S, Levilliers J, Weissenbach J, Belkahia A, Petit C. A non-syndrome form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat Genet.1994;6:24-28.
12. Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM. Connexin 26 mutations n hereditary non-syndromic sensorineural deafness. Nature.1997;387:80-83.
13. Kenneson A, Van Naarden Braun K, Boyle C. GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss:a HuGE review. Genet Med.2002;4:258-274.
14. de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, Huber I, Monaco AP, Malcolm S, Pembrey ME, Ropers HH, Cremers FP. Association between X-linked mixed deafness and mutations in the POU domain genePOU3F4. Science.1995;267:685-688.
15. Gorlin RJ, Toriello HV, Cohen MM. Hereditary Hearing Loss and its Syndromes. Oxford University Press; New York:
16. Lenz DR1, Avraham KB. Hereditary hearing loss:from human mutation to mechanism. Hear Res.2011;281(1-2):3-10.
17. Phelps PD, Coffey RA, Trembath RC,et al. Radiological malformations of the ear in Pendred syndrome. Clin Radiol.1998;53:268-273.
18. Everett LA, Glaser B, Beck JC,et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet.1997; 17:411-422.
19. Campbell C, Cucci RA, Prasad S,et al. Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutation and possible genotype-phenotype correlations. Hum Mutat.2001;14:404-411.
20. Scott DA, Wang R, Kreman TM,et al. The Pendred syndrome gene encodes a chloride-iodide transport protein. Nat Genet.1999;21(4):440-443.
21. Azaiez H, Yang T, Prasad S,et al. Genotype-phenotype correlations for SLC26A4-related deafness. Hum Genet.2007; 122(5):451-457.
22. S Chatkupt, S Chatkupt, W G Johnson. Waardenburg syndrome and myelomeningocele in a family J Med Genet.1993 January; 30(1):83-84.
23. A P Read, V E Newton. Waardenburg syndrome.J Med Genet.1997 August; 34(8):656-665.
24. Filiz Hazan, A.Taylan Ozturk, Hamit Adibelli, et al. A novel missense mutation of the paired box 3 gene in a Turkish family with Waardenburg syndrome type 1Mol Vis.2013; 19: 196-202.
25. Sandy Leger, Xavier Balguerie, Alice Goldenberg,et al. Novel and recurrent non-truncating mutations of the MITF basic domain:genotypic and phenotypic variations in Waardenburg and Tietz syndromes. Eur J Hum Genet.2012; 20(5):584-587
26. N.M. Haddad, D. Ente, E. Chouery, N. Jalkh, et al. Molecular Study of Three Lebanese and Syrian Patients with Waardenburg Syndrome and Report of Novel Mutations in theEDNRB and MITF Genes.Mol Syndromol.2011 January; 1(4):169-175.
27. Friedman TB, Schultz JM, Ahmed ZM,et al. Usher syndrome:hearing loss with vision loss.Adv Otorhinolaryngol.2011;70:56-65.
28. Bonnet C, El-Amraoui A. Usher syndrome_(sensorineural deafness and retinitis pigmentosa): pathogenesis, molecular diagnosis and therapeutic approaches.Curr Opin Neurol. 2012;25(1):42-9.
29. Yan D, Liu XZ. Genetics and pathological mechanisms of Usher syndrome.J Hum Genet. 2010;55(6):327-35.
30. Earl TJ, Khan L, Hagau D,et al. The spectrum of aortic pathology in_alport syndrome:a case report and_review_of the literature.Am J Kidney Dis.2012;60(5):821-822.
31. Kruegel J, Rubel D, Gross O. Alport syndrome--insights from basic and clinical research.Nat Rev Nephrol.2013;9(3):170-178.
32. Yuanfeng Gao, Cuilan Li, Wenling Liu,et al. Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome. J Cardiovasc Dis Res.2012; 3(2):67-75.
33. Jae Suk Baek, Eun Jung Bae, Sang Yun Lee,et al. Jervell and Lange-Nielsen Syndrome: Novel Compound Heterozygous Mutations in the KCNQ1 in a Korean Family. J Korean Med Sci.2010; 25(10):1522-1525.
34. Renjian Zheng, Keith Thompson, Edmond Obeng-Gyimah, et al. Analysis of the interactions between the C-terminal cytoplasmic domains of KCNQ1 and KCNE1 channel subunits.Biochem J.2010; 428(1):75-84.
35. Maddalena Gigante, Marilena d'Altilia, Eustacchio Montemurno,et al. Branchio-Oto-Renal Syndrome (BOR) associated with focal glomerulosclerosis in a patient with a novel EYA1 splice site mutation.BMC Nephrol.2013; 14:60.
36. Amarilis Sanchez-Valle, Xueqing Wang, Lorraine Potocki, et al. HERV-Mediated Genomic Rearrangement of EYA1 in an Individual With Branchio-oto-renal Syndrome.Am J Med Genet A.2010; 152A(11):2854-2860.
37. Kaneto CM, Lima PS, Zanette DL,et al. COL1A1 and miR-29b show lower expression levels during osteoblast differentiation of bone marrow stromal cells from Osteogenesis Imperfecta patients.BMC Med Genet.2014;15(1):45
38. Stephen J, Shukla A, Dalal A,et al. Mutation spectrum of COL1A1 and COL1A2 genes in Indian patients with osteogenesis imperfecta.Am J Med Genet A.2014; 164(6):1482-9.
39. Izumi K, Konczal LL, Mitchell AL, Jones MC. Underlying genetic diagnosis of Pierre Robin sequence:retrospective chart review at two children's hospitals and a systematic literature review.J Pediatr.2012;160(4):645-650.
40. Li K, Thorne C. Adult presentation of.Stickler syndrome type Ⅲ.Clin Rheumatol. 2010;29(7):795-7.
41. Snead MP, McNinch AM, Poulson AV,et al. Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist.Eye (Lond).2011;25(11):1389-400.
42. Evans GR, Lloyd SK, Ramsden RT. Neurofibromatosis type 2.Adv Otorhinolaryngol. 2011;70:91-8.
43. Blakeley JO, Evans DG, Adler J,et al. Consensus recommendations for current treatments and accelerating clinical trials for patients with neurofibromatosis type 2.Am J Med Genet A. 2012 Jan;158A(1):24-41.
44. Lloyd SK, Evans DG. Neurofibromatosis type 2 (NF2):diagnosis and management.Handb Clin Neurol.2013:115:957-67.
45. Chang CC, Steinbacher DM. Treacher collins syndrome.Semin Plast Surg.2012;26(2):83-90.
46. Konstantinidou AE, Tasoulas J, Kallipolitis G,et al. Mandibulofacial dysostosis (Treacher-Collins syndrome) in the fetus:novel association with Pectus carinatum in a molecularly confirmed case and_review_of the fetal phenotype.Birth Defects Res A Clin Mol Teratol.2013;97(12):774-780.
47. Kadakia S, Helman SN, Badhey AK, et al. Treacher Collins Syndrome:The genetics of a craniofacial disease.Int J Pediatr Otorhinolaryngol.2014;78(6):893-898.
1. 迟放鲁,王璟,袁雅生,等.中耳手术中的面神经定位.中华耳鼻咽喉头颈外科杂志,2006,41(1)：5-8.
2. Raine CH,Hussain SS,Khan S,et al. Anomaly of the facial nerve and cochlear implantation. Ann Otol Rhinol Laryngol Suppl,1995,166:430-431.
3. Arnoldner C, Baumgartner WD, Gstoettner W,et al. Surgical considerations in cochlear implantation in children and adults:a review of 342 cases in Vienna. Acta Otolaryngol, 2005,125(3):228-234.
4. Song JJ, Park JH, Jang JH,et al. Facial nerve aberrations encountered during cochlear implantation. Acta Otolaryngol,2012,132(7):788-794.
5. Fayad JN, Wanna GB, Micheletto JN,et al. Facial nerve paralysis following cochlear implant surgery. Laryngoscope,2003,113(8):1344-1346.
6. 朱杭军,廖建春,王海清,等.鼓索神经颞骨部的解剖及临床应用.解剖与临床,2003,8(4)：201-202.
7. Jeon EJ, Jun B, Song JN,et al. Surgical and radiologic anatomy of a cochleostomy produced via posterior tympanotomy for cochlear implantation based on three-dimensional reconstructed temporal bone CT images. Surg Radiol Anat,2013 Jan 3.
8. Calli C, Pinar E, Oncel S,et al. Measurements of the facial recess anatomy:implications for sparing the facial nerve and chorda tympani during posterior tympanotomy. Ear Nose Throat J,2010,89(10):490-494.
9. 李健东,李娟,汪学勇,等.面神经减压术中鼓索解剖观察及临床意义.中国临床解剖学杂志,20]1,29(1)：7-9.
10. McManus LJ, Stringer MD, Dawes PJ. Iatrogenic injury of the chorda tympani:a systematic review. J Laryngol Otol,2012,126(1):8-14.
11. Guinand N, Just T, Stow NW,et al. Cutting the chorda tympani:not just a matter of taste. J Laryngol Otol,2010,124(9):999-1002.
12. Bielamowicz SA, Coker NJ, Jenkins HA, et al. Surgical dimensions of the facial recess in adults and children.Arch Otolaryngol Head Neck Surg,1988,114(5):534-537.
13.何利平,贺飞,李永新,等.人工耳蜗植入相关的解剖学研究.耳鼻咽喉头颈外科,2002,9(3)：168-170.
14. Su WY,Marion MS,Hinojosa R,et al.Anatomical measurements of the cochlear aqueduct,round window_membrane,round windowniche, and facial recess. Laryngoscope,1982,92(5):483-486.
15.张道行.人工耳蜗电极植入耳蜗入口的定位.临床耳鼻咽喉科杂志,2000,14(5)：195-196.
16.王明辉,张秋贵,张晓恒,等.经乳突-面隐窝径路人工耳蜗植入术解剖学研究.青岛大学医学院学报,2009,45(03)：267-268+271.
17.邹团明,郭梦和,张宏征,等.人工耳蜗植入术鼓阶入口定位的相关解剖研究.南方医科大学学报,2012,32(6)：904-907.
18. Trinh BT, Bergeron F, Ferron P. Long-term follow-up of cochlear implant users with ossified cochlea. J Otolaryngol,2000,29(5):279-284.
19. Hodges AV, Balkany TJ, Gomez-Marin O, et al.Speech recognition after implantation of the ossified cochlea. Am J Otol,1999,20(4):453-456.
20. Nadol JB Jr. Patterns of neural degeneration in the human cochlea and auditory nerve: implications for cochlear implantation. Otolaryngol Head Neck Surg,1997,117(3 Pt 1): 220-228.
21. Balkany T, Gantz BJ, Steenerson RL,et al. Systematic approach to electrode insertion in the ossified cochlea. Otolaryngol Head Neck Surg,1996,114(1):p.4-11.
22. Young NM, Hughes CA, Byrd SE, et al. Postmeningitic ossification in pediatric cochlear implantation. Otolaryngol Head Neck Surg,2000,122(2):183-188.
23. Berrettini S, Forli F, Neri E, et al. Scala vestibuli cochlear implantation in patients with partially ossified cochleas. J Laryngol Otol,2002,116(11):946-950.
24. Taibah K. The transmeatal approach:a new technique in cochlear and middle ear implants. Cochlear Implants Int,2009,10(4):218-228.
25. Postelmans JT, Tange RA, Stokroos RJ,et al. The suprameatal approach: a safe alternative surgical technique for cochlear implantation. Otol Neurotol,2010,31(2):196-203.
26. Ozturan O, Bauer CA, Miller CC 3rd,et al. Dimensions of the sinus tympani and its surgical access via a retrofacial approach. Ann Otol Rhinol Laryngol,1996,105(10):776-783.