常染色体显性遗传非综合征性耳聋家系临床听力学特征分析及致病基因定位研究

目的 分析一个连续六代遗传的耳聋家系临床听力学特征及遗传特征,应用连锁分析的方法定位致聋基因.方法 通过家系调查,对一个高频感音神经性聋家系的资料进行了收集、整理及临床听力学和遗传学特征的分析.对家系成员进行调查并绘制系谱图.对调查的家系成员进行病史采集、体检、纯音测听和声导抗检查.结果 该耳聋家系遗传方式为常染色体显性遗传,耳聋患者表现为语后、迟发、渐进、以高频下降为主的听力损失,早期以高频听力损失为主,随着年龄增长逐渐累及全频听力,听力曲线由下降型变为平坦型.结论 该耳聋家系为常染色体显性遗传方式,表现为高频感音神经性耳聋,通过全基因组SNP扫描及连锁分析,初步定位于4号染色体190384723-190669832区域.     

常染色体显性遗传耳聋家系听力学及遗传学特征分析

目的分析一个常染色体显性遗传性耳聋家系的听力学及遗传学特征,制定致聋基因鉴定策略。方法对该常染色体显性遗传性耳聋家系进行问卷调查,听力学检测,绘制该耳聋家系的遗传图谱,分析其听力学及遗传学特征。结果该家系共5代,进行听力学检测者为33人,听力下降者19人.听力学表现为双侧对称的感音神经性耳聋,以高频听力损失为主,听力损失呈进行性加重,但该家系内2个不同分支听力下降时间明显不同,分别为10-30岁和60岁。该家系A组符合常染色体显性遗传感音神经性耳聋特点,B组符合显性遗传老年性聋特点。结论这个家系的两组成员分别表现出2种不同的听力学表型。A组成员为高频听力下降为主的感音神经性耳聋,符合常染色体显性遗传非综合征型耳聋特点;B组成员为高频听力下降为主的老年性聋,符合显性遗传规律,这2组成员可能分别由不同的致病基因导致,需要根据各自的听力学表型及遗传学特征分别制定耳聋基因筛查策略。     

进行性非综合征型聋家系临床表型及遗传学分析

目的分析一个连续五代常染色体显性遗传性非综合征型聋家系的临床表型及遗传学特征。方法对该耳聋家系成员进行病史采集、全身及听力学检查,绘制遗传图谱并进行遗传学特征分析。应用微卫星标记连锁分析方法及外显子序列分析对常染色体显性遗传(DFNA)23个基因的22个位点进行初步筛查。结果该耳聋家系共五代,现存家系成员44人,参与本研究的39人中耳聋患者16人,除1人为语前聋外,其他患者均表现为迟发性、渐进性听力下降,发病年龄介于14～40岁,早期以中频听力下降为主,逐渐累及高频,随着年龄的增长,呈全频听力下降。除DFNA5外,各DFNA位点连锁分析所得LOD值均<-2,提示该家系的致聋基因与这些位点均不连锁。对家系中2例患者和2例正常者DFNA5的所有外显子进行测序分析,未发现突变。结论该家系遗传方式符合常染色体显性遗传规律,表现为以中高频听力下降为主的感音神经性聋;对已知耳聋基因位点进行筛查,未发现明确的阳性位点;通过新一代测序技术进行全外显子组分析可能发现新的感音神经性聋致病基因。     

一个常染色体显性遗传低频感音神经性聋家系听力学及遗传学特征分析

目的分析一个常染色体显性遗传性聋家系的临床听力学特征及遗传规律。方法对一个常染色体显性遗传低频感音神经性聋家系28名成员进行病史采集、体检及纯音测听、声导抗检查并绘制系谱图。其中,5名患者进行耳声发射、听性脑干反应检查,2名患者进行前庭功能及颞骨CT扫描检查以排除听神经病及听觉系统的其他病变。全部成员均应用微卫星标记对DFNA21个位点23个基因进行初步筛查,数据分析采用连锁分析方法。结果该耳聋家系（命名为BJ—L046）遗传方式为常染色体显性遗传,耳聋患者表现为迟发型的、渐进性的、以低频下降为主的听力损失,发病年龄5～28岁,早期以低频损失为主,听力曲线呈上升型,随着年龄增长逐渐累及全频听力,听力曲线由上升型变为平坦型。全部家系成员FNA21个位点23个基因筛查均为阴性。结论该耳聋家系为常染色体显性遗传方式,表现为低频感音神经性聋,数据连锁分析无阳性发现,初步排除了21个DFNA位点23个已知基因。     

一个常染色体显性遗传非综合征性聋家系分析

目的:分析一个连续5代遗传的常染色体显性高频听力损失家系的听力学及遗传学特征。方法:通过对家系成员进行全面体检及临床听力学检测,整理、分析家系资料,确定遗传规律,绘制遗传图谱并进行听力学特征分析。应用Affymetrix 5.0SNP芯片对该家系参与连锁分析的32例成员进行全基因组扫描及连锁分析,行致病基因的染色体定位。结果:该耳聋家系(命名为SX-G087)成员共计91例。其先证者为感音神经性聋,无全身其他系统异常。耳聋遗传方式为常染色体显性遗传,发病年龄各代间较稳定,为20～35岁。听力表型为代代相传、迟发性、渐进性的中度至重度听力损失,以高频下降为主,部分患者随着年龄增长逐渐累及全频听力,听力曲线由下降型变为平坦型。应用芯片进行全基因组扫描,1～22号染色体未发现有显著连锁的区段。结论:该家系遗传学特征符合常染色体显性遗传方式,表现为早期高频听力下降并逐渐累积全频的特征,全基因组扫描未发现有显著连锁的区段。因此希望通过对该家系进一步的表型分析或者运用新一代测序技术,可以找到该家系高频感音神经性聋的致病基因。     

一个常染色体显性遗传非综合征型聋家系的听力学及遗传学特征分析

目的 分析一个常染色体显性遗传非综合征型聋家系的听力学和遗传学特征.方法 对收集到的一个常染色体显性遗传非综合征型聋家系成员进行家系调查、听力学检测和全身体格检查,绘制家系图谱,整理、分析家系成员的听力学和遗传学特征;提取外周血DNA,对已知常见耳聋基因GJB2、GJB3、COCH、EYA4以及线粒体DNA全序列进行筛查.结果 该家系由5代53名成员组成,现存4代42人,耳聋患者11人;耳聋表型连续遗传,男女均可患病,符合常染色体显性遗传规律,均表现为对称性语后感音神经性聋(12～36岁之间发病),起初为高频听力下降,随着年龄的增长,逐渐累及中低频听力.已知常见致聋基因全编码序列突变检测分析无阳性发现.结论 该常染色体显性遗传非综合征型聋家系中耳聋者表现为对称性、迟发性、进行性、高频下降为主的语后感音神经性聋.     

特大常染色体显性遗传聋家系听力学特征及候选致病基因突变筛查

目的探讨一中国常染色体显性遗传聋大家系的听力学特征,进行已知致聋基因已知突变位点的筛查。方法经知情同意,对家系成员进行全身检查及听力学检测,获得血样标本;整理分析家系资料并绘制系谱图;用基因组DNA抽提试剂盒提取外周血DNA。对2例家系患者DNA进行GJB2和GJB3基因全部编码区突变检测,对其余23个已知常染色体显性遗传性耳聋(DFNA)基因的74个已知突变位点所涉及的50个外显子进行PCR扩增和直接测序分析。结果该家系共7代199人,现存4代176人,耳聋患者54人。系谱分析显示,耳聋表型代代相传,男女患病人数分别为24和30,符合常染色体显性遗传特征。听力学表现为:迟发性、进行性、双侧对称性、感音神经性听力损失,首先是高频区受损,并快速向中、低频扩展。GJB2、GJB3基因全部编码区及其余23个DFNA基因已知突变位点的序列分析均无阳性发现。结论该家系是一个非综合征型常染色体显性遗传聋大家系,耳聋表型为迟发性、进行性、双耳对称性感音神经性听力损失;初步分子遗传学分析提示可能由新基因或已知基因的新突变致病。     

一个常染色体显性遗传非综合征型聋家系分析

目的分析一个连续5代遗传的常染色体显性遗传性聋家系的临床听力学及遗传学特征。方法对一个常染色体显性遗传高频感音神经性聋家系成员进行全面体检及临床听力学检查,整理、分析家系资料,确定遗传规律,绘制遗传图谱并进行听力学特征分析。应用Sanger测序技术对该家系成员进行候选基因鉴定。结果该耳聋家系遗传方式为常染色体显性遗传,发病年龄各代间较稳定,在30-45岁之间。听力学表型为代代相传、迟发性、渐进性的中度至重度听力损失,患者早期以高频听力下降为主,随着年龄增长逐渐累及全频听力。应用Sanger测序技术进行候选基因鉴定,未发现致聋突变位点。结论该家系遗传学特征符合常染色体显性遗传方式,听力学具有早期高频听力下降并逐渐累及全频的特征,在候选基因中进行测序未发现致聋突变位点。因此希望通过对家系进一步的表型分析或者运用新一代测序技术,可以找到该家系的致聋基因。     

一噪声相关常染色体显性遗传耳聋家系遗传性分析

目的分析一个与噪声接触相关的常染色体显性遗传性耳聋家系的听力学及遗传学特征,制定致聋基因鉴定策略。方法对该常染色体显性遗传性耳聋家系进行问卷调查,听力学检测及全身体查,绘制该耳聋家系的遗传图谱,分析其听力学及遗传学特点。应用Sanger测序技术进行候选基因鉴定。结果该家系共5代,进行听力学检测者为13人,听力下降者6人,其中3人有明显的噪声接触史。听力学表现为双侧迟发性感音神经性耳聋,先以高频听力损失为主,随后逐渐加重累及全频听力下降,听力开始下降年龄在16-37岁之间。起病后3年症状明显加重。应用Sanger测序技术进行候选基因鉴定,未发现致聋突变位点。结论这个家系成员为高频听力下降为主的迟发性感音神经性耳聋,符合常染色体显性遗传非综合征型耳聋特点,且怀疑有噪声易感因素。计划下一步通过对家系的表型分析运用新一代测序技术希望鉴定出该家系的致聋基因。     

一个中国河北省遗传性低频感音神经性耳聋家系临床表型及遗传学特征分析

目的分析一个常染色体显性遗传性耳聋家系的临床听力学特征及遗传规律。方法对一个国人常染色体显性遗传低频感音神经性耳聋家系的资料进行了收集、整理及临床遗传学特征的分析。对家系成员进行调查并绘制系谱图。对调查的家系成员进行病史、体检、纯音测听、声导抗检查,两名患者进行耳声发射、听性脑干反应、前庭功能及颞骨CT扫描检查以排除听神经病及听觉系统的其他病变。结果该耳聋家系遗传方式为常染色体显性遗传,耳聋患者表现为一种迟发型的、渐进性的、以低频下降为主的听力损失,发病年龄介于10～25岁,早期以低频损失为主,听力曲线呈上升型,随着年龄增长逐渐累及全频听力,听力曲线由上升型变为平坦型。结论该耳聋家系为常染色体显性遗传方式,表现为低频感音神经性耳聋,通过全基因组扫描及连锁分析,有望发现新的低频感音神经性聋的相关基因。     

Phenotypic characterization of hereditary hearing impairment linked to DFNA25

OBJECTIVES: To clinically characterize a family with nonsyndromic sensorineural hearing loss linked to the DFNA25 gene and to assess whether mitochondrial mutations influence the penetrance of the phenotype. DESIGN: Longitudinal clinical and basic science molecular genetic study. SETTING: Academic medical center and molecular genetic research laboratory. PARTICIPANTS: Members of a family with dominant high-frequency sensorineural hearing loss. INTERVENTIONS: Questionnaires, serial audiograms, and interviews correlated with molecular genetic data. MAIN OUTCOME MEASURES: Symptoms, age at onset, serial audiometric data, and the presence or absence of 4 deafness-associated mitochondrial mutations. RESULTS: Affected individuals typically manifest a high-frequency, slowly progressive sensorineural hearing loss in the postlingual period. The mode of inheritance is autosomal dominant with age-dependent penetrance. Male affected members tended to report an earlier onset of hearing loss than female members. In those inheriting the DFNA25-associated haplotype from an affected mother, hearing loss invariably developed by the second decade of life, whereas those inheriting the DFNA25 haplotype from an affected father often maintained hearing levels comparable to those of age-matched control subjects, even into the seventh decade of life. None of 4 deafness-associated mitochondrial mutations screened (1555A>G, 7445A>G, Cins7472, and 7511T>C) were found to segregate in the family. CONCLUSIONS: It is difficult to differentiate delayed-onset high-frequency sensorineural hearing loss inherited as a simple mendelian trait like DFNA25-associated hearing loss from that due to noise exposure or presbycusis, disorders that may also have a genetic component. An awareness of the clinical presentation of such hearing loss may help clinicians identify hearing loss attributable to genetic causes and improve care for these patients.     

1个DFNA5家系临床遗传学特点及听力学特征分析

目的:对1个DFNA5大家系的临床遗传学特点及听力学特征进行分析.方法:通过整理分析家系资料,确定该家系的遗传方式为常染色体显性遗传,对家系成员的临床特点进行分析,对比研究该家系成员听力受损与年龄增长之间的关系.结果:该家系是一个分布于5代、成员共42例(包括已故和配偶)的常染色体显性遗传性聋家系,听力学特征表现为早期以高频损失为主,听力曲线多呈"Z"型,随着年龄增长,逐渐演变为斜坡形听力曲线.最终导致全频听力逐渐下降.结论:该家系是一个常染色体显性遗传的DFNA5大家系,听力学具有早期高频听力下降并逐渐累积全频的特征,这一特征与年龄相关性听力损失的频率特性很相似,因此具备该类听力特点的遗传性聋应考虑到DFNA5基因突变的可能.     

Follow-up study in a family with dominant progressive hereditary sensorineural hearing impairment. I. Analysis of hearing deterioration

An autosomal-dominant progressive hereditary sensorineural hearing loss with onset in the high frequencies was studied in a Dutch family with 105 affected individuals. The hearing loss was analyzed by a curve-fitting procedure. A hyperbolic tangent was fitted into the audiogram. Five characteristics were distinguished: the high-frequency plateau, the low-frequency plateau, the slope, the low cut-off frequency and the high cut-off frequency. Six phases are recognizable in the development of the hearing loss, which is characterized by a two-step progression, first in the high and then in the low frequencies. Great differences in the rate of the deterioration were observed. The age of onset is between 5 and 15 years.     

Frequency selectivity and consonant intelligibility in sensorineural hearing loss

The relations between frequency selectivity and consonant intelligibility were investigated in subjects with sensorineural hearing loss in an attempt to derive predictive indices. Three matched pairs of subjects with similar audiometric configurations (high-frequency, flat or low-frequency hearing loss) but significantly different word-intelligibility scores were tested. Characteristics of psychophysical tuning curves (PTCs) for high- and low-frequency probes were compared with speech-intelligibility performance for high- and low-frequency consonant-vowel syllables. Frequency-specific relations between PTC characteristics and consonant-intelligibility performance were observed in the subject pairs with high-frequency and flat sensorineural hearing loss. Corresponding results for the subject pair with low-frequency sensorineural hearing loss were equivocal.     

Prevalence of the A1555G MTDNA mutation in sporadic hearing-impaired patients without known history of aminoglycoside treatment

IntroductionThe A1555G mitochondrial DNA (mtDNA) mutation is responsible for maternally inherited non-syndromic hearing loss that is increased by aminoglycoside exposure. The objective of this study was to ascertain the frequency of the A1555G mutation among patients without family history of hearing loss or known exposition to aminoglycosides.MethodsWe screened for the mtDNA A1555G mutation in Spanish patients with sporadic sensorineural hearing impairment without a known family history of hearing loss or aminoglycoside exposition seen at the ENT Department in Sierrallana Hospital (Torrelavega, Cantabria, Spain) over a four-year period.ResultsA total of 219 patients with bilateral hearing loss were screened. Two of them (0.9%) had the A1555G mitochondrial DNA mutation. Both patients had a moderate bilateral sensorineural hearing loss for low frequency, and moderate to severe loss for high-frequency.ConclusionsThe mtDNA A1555G mutation in patients with sensorineural hearing loss without family history of deafness or aminoglycoside ototoxicity is infrequent in our region. We should suspect this mutation in patients younger than 50 years old, with postlingual bilateral sensorineural hearing loss that is more pronounced at high frequency.     

梅毒性感音神经性聋的临床分析

目的:探讨梅毒性感音神经性聋的临床表现、诊断和治疗.方法:回顾性分析3例梅毒性感音神经性聋患者的临床症状、体征、血清学及治疗.结果:3例梅毒性感音神经性聋患者中,2例RPR和TPPA均阳性;1例RPR阴性,TPPA阳性;2例在外院已确诊为梅毒并行驱梅治疗;2例为突发性聋起病,伴有耳鸣,1例为耳鸣起病伴高频听力下降.均已排除了其他原因所致的:千聋耳鸣,治疗后听力无改善.结论:梅毒性感音神经性聋可以突发性聋或耳鸣发病,易漏诊.对病因不明的听方下降,伴有耳鸣、眼球震颤的患者,应行必要的实验室检查以明确诊断.     

Mutations in the Wolfram syndrome type 1 gene (WFS1) define a clinical entity of dominant low-frequency sensorineural hearing loss

OBJECTIVE: To describe low-frequency sensorineural hearing loss (LFSNHL) inherited as a dominant trait in 3 families and in 1 sporadic case. DESIGN: Longitudinal clinical study from 1968 to 2001. SETTING: Tertiary care hospital; field studies conducted by molecular genetic research laboratory. PARTICIPANTS: Dominant LFSNHL families. INTERVENTIONS: Questionnaires, serial audiograms, and interviews, correlated with molecular genetic data. OUTCOME MEASURES: Symptoms, age of onset, serial audiometric data, and hearing aid use. RESULTS: Low-frequency sensorineural hearing loss is typically diagnosed in the first decade and slowly progresses over decades; LFSNHL is often asymptomatic in young patients, few of whom use hearing aids. Speech perception becomes affected in later decades when patients develop high-frequency loss. Even children with a strong family history of dominant LFSNHL were not monitored routinely. Penetrance appears complete in that all individuals with a genetic mutation developed hearing loss. CONCLUSIONS: Dominant LFSNHL is most commonly caused by mutations in the Wolfram syndrome type 1 gene (WFS1). Mutations in WFS1 also cause a rare recessive syndromic form of hearing loss known as Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Routine newborn hearing screening methods will not typically identify hearing loss affecting frequencies below 2000 Hz; thus, children at risk must be specifically monitored. Genetic counseling and genetic testing may be useful in the management of patients with this type of hearing loss.