中国散发感音神经性聋患者GJB2基因突变的筛查分析
发布时间：2019-06-30 21:31
【摘要】： 感音神经性聋是人类最常见的先天性疾患之一,也是耳科门诊最常见的疾患之一,由遗传、老化、耳毒性药物、感染及噪声等多因素共同作用而形成。据文献报道,新生儿的耳聋发病率高达1-3/1000；在先天性耳聋中,有50%是由于遗传因素引起的,其中70-80%是常染色体隐性遗传,而50%的常染色体隐性遗传性耳聋是与GJB2基因突变有关。自1997年第一个GJB2致耳聋突变被报道以来,已经发现超过150个GJB2基因突变,其中,60%是常染色体隐性遗传,20%的突变对听力的影响不明确。据不同文献报道,GJB2突变的频率有种族特异性。例如,高加索人群最常见突变为35delG,犹太人群为167delT,而东亚人群最常见突变为235delC。我国的感音神经性聋患者绝对数量超过8千万,占耳聋患者的63%。我院耳科门诊有可达2-10%的患者是由于单纯双侧感音神经性聋而就诊。近几年来,我国多个中心均展开了在聋哑学校为主的对GJB2基因突变的筛查,也指出了235delC为我国最常见的GJB2致聋突变,检出率高达13%'21%,常见的多态性突变(SNP)如79GA,有争议的突变如109GA。但是针对散发的门诊耳聋患者,尤其是对轻到中度耳聋患者的GJB2突变筛查,以及其致聋临床特征的描述尚比较缺乏。因此,在我国门诊散发感音神经性聋患者中开展筛查,将GJB2基因突变检测从中度、极重度聋患者推广到轻、中度聋患者,将对耳聋的临床及产前诊断和遗传咨询以及完善遗传性耳聋的流行病学数据库有重要意义。 目的：了解门诊散发感音神经性聋患者的GJB2基因突变情况以及与听力表型的关系。方法：对2008年5月29日到2010年3月25日来我院耳科门诊就诊的233名感音神经性聋患者及其85名有血缘关系的直系亲属,以及100名听力正常的志愿者进行GJB2基因编码区和线粒体12 SrRNA突变筛查。结果：233名患者中,172名(73.8%)检测到GJB2基因序列改变,109GA携带者57例(24.5%),等位基因频率17.4%; 235delC携带者25例(10.7%),等位基因频率6.9%。47例(20.2%)考虑为GJB2基因突变致聋,5例(2.1%)考虑与线粒体DNA致聋突变有关。检出GJB2序列改变17种,新突变4种。在GJB2致病突变中,最常见的是109GA(32例),占GJB2相关性耳聋患者的68.1%,包括纯合24例,占患者的10.3%,占GJB2相关性耳聋患者的51.1%。其次为235delC(18例),占GJB2相关性耳聋患者的38.3%, 235delC纯合突变7例,只占患者的3%,占GJB2相关性耳聋患者的14.9%。299-300delAT相关的病例4例,占GJB2相关性耳聋患者的8.5%,包括299-300delAT纯合1例。患者组检出复合杂合致病突变15例,包括109GA/235delC 4例,109GA/299-300delAT 1例,109GA/427CT 2例,235delC/299-300delAT 3例,176dell6/235delC、235delC/504insAACG、235delC/605ins46、235delC/257C＞G、79GA,109GA/478GA各1例。在患者亲属组及正常对照组均未发现109GA纯合突变或含109GA的复合杂合致病突变,只发现109GA杂合突变(15例和6例)。线粒体DNA致病突变包括1555AG3例,1494CT1例,1519insCA 1例。结论：1.GJB2109GA是散发感音神经性聋患者的最常见的致病突变,并以常染色体隐性形式遗传致病。列第二、三位的分别为235delC,299-300delAT。2.发病特点：235delC纯合患者的发病年龄较早,85.7%在出生到5岁之前,病情较重,42.9%为重到极重度听力损失,听力曲线57.1%为平坦型；109GA纯合子患者发病年龄稍晚,从5到47岁不等,在各年龄段均有分布,病情较轻,95.8%为轻到中度听力损失,听力曲线87.5%为下降型。3.79GA+341AG是多态性改变。4.认为257CG,478GA为致病突变；368CA突变性质不明确；新发现的突变位点65AC,88AG,380GT,494GA各一例,均为杂合突变,其功能尚不明确。
[Abstract]:Sensorineural hearing loss is one of the most common congenital diseases in the human body, and is one of the most common diseases in the ear-care clinic, which is formed by the combination of genetic, aging, ototoxic drugs, infection and noise. According to the literature, the incidence of deafness in the newborn is as high as 1-3/1000; in the case of congenital deafness,50% is caused by genetic factors, of which 70-80% are autosomal recessive inheritance, while 50% of the autosomal recessive hereditary deafness is related to the GJB2 gene mutation. Since the first GJB2-induced deafness mutation in 1997, more than 150 GJB2 gene mutations have been found, of which 60% are autosomal recessive inheritance and 20% of the mutations are not clear to the hearing. According to different literature, the frequency of GJB2 mutation is of racial specificity. For example, the most common mutation in the Caucasian population is 35 delG, the Jewish population is 167 delT, and the most common mutation in the East Asian population is 235delC. The absolute number of sensorineural hearing loss in our country is over 80 million, accounting for 63% of the patients with deafness. The patients with 2-10% of the outpatients in our hospital were treated due to simple bilateral sensorineural hearing loss. In recent years, many centers in China have conducted screening of GJB2 gene mutation in the deaf-mute school, and also pointed out that 235delC is the most common deafness mutation of GJB2 in China. The detection rate is as high as 13% '21%, and the common polymorphism mutation (SNP) such as 79GA, and the controversial mutation such as 109 GA. However, the GGJB2 mutation screening, especially for patients with mild to moderate deafness, and the description of its deafness clinical features are not yet available for patients with outpatients with hearing loss, especially those with mild to moderate deafness. Therefore, screening is carried out in the patients with sensorineural hearing loss in our clinic, and the GJB2 gene mutation detection is extended to the patients with mild and moderate deafness from the patients with moderate and extremely severe deafness, It is of great significance to clinical and prenatal diagnosis and genetic counseling for deafness and to improve the epidemiological database of genetic deafness. Objective: To study the GJB2 gene mutation in the patients with sensorineural hearing loss and the hearing phenotype. Methods: A total of 233 sensorineural hearing-deaf patients and 85 direct-family members with a blood-related relationship were visited from May 29,2008 to March 25,2010, and the GJB2 gene coding region and the mitochondrial 12SrRNA process were performed in 100 patients with normal hearing. Results: Of the 233 patients,172 (73.8%) of the 233 patients were detected to change the GJB2 gene,57 cases (24.5%) of the 109 GA carriers, 17.4% of the allele frequency, and 25 (10) of the 235delC carriers. The frequency of allele was 6.9%.47 (20.2%) of 47 cases (20.2%) considered to be deaf to GJB2 gene mutation,5 (2.1%) considered to be deaf to the mitochondrial DNA The changes of GJB2 were detected and 17 new processes were detected. Among the pathogenic mutations of GJB2, 109GA (32 cases), accounting for 68.1% of GJB2-related deafness, including 24 cases of homozygous, 10.3% of the patients, and 51 of the patients with the GJB2-related deafness. 1%. The second was 235delC (18 cases), accounting for 38.3% of GJB2-related deafness patients and 7 cases of 235delC homozygosity, accounting for 14.9% of the patients with GJB2-related deafness, and 4 cases related to 299-300delAT, accounting for 8.5% of the patients with GJB2-related deafness, including 299-300delAT pure. In 1 case,15 cases were detected in the patient group, including 109 GA/235 delC 4 cases,109 GA/299-300delAT 1 case,109 GA/ 427CT 2 cases, 235delC/299-300delAT 3 cases, 176dell6/ 235delC, 235delC/ 504insAACG, 235delC/ 605ins46, 235delC/ 257C.G, 79GA, 109GA/ 478GA One case was found.109 GA homozygous mutation or 109-GA-containing compound heterozygous mutation was found in the patient's relative group and the normal control group, and only 109 GA heterozygous mutations were found (15 cases). 6 cases). The mitochondrial DNA pathogenic mutation included 1555AG3, 1494CT1 and 1519insC. Conclusion:1. GJB2109GA is the most common pathogenic mutation in the patients with sensorineural hearing loss, and it is a recessive form of autosomal recessive. The second and the third are 235delC,299-300delA, respectively. T.2. The characteristic of the disease: the onset age of the 235delC homozygote is earlier, and 85.7% is more severe, 42.9% is the most severe hearing loss before the birth to the age of 5, the hearing curve 57.1% is of the flat type, the incidence age of the 109 GA homozygote is slightly late, the age of 5 to 47 years old, and the like, There were distribution, mild condition, 95.8% of mild to moderate hearing loss, 87.5% of the hearing curve was down type, 3.79 GA + 341 AG was the change of the polymorphism Varied.4. It is considered that the mutation of 257CG and 478GA is a pathogenic mutation; the mutation property of 368CA is not clear; the newly discovered mutation sites 65AC, 88AG, 380GT and 494GA are all heterozygous mutations, and its function is still
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2010
【分类号】：R764
[Abstract]:Sensorineural hearing loss is one of the most common congenital diseases in the human body, and is one of the most common diseases in the ear-care clinic, which is formed by the combination of genetic, aging, ototoxic drugs, infection and noise. According to the literature, the incidence of deafness in the newborn is as high as 1-3/1000; in the case of congenital deafness,50% is caused by genetic factors, of which 70-80% are autosomal recessive inheritance, while 50% of the autosomal recessive hereditary deafness is related to the GJB2 gene mutation. Since the first GJB2-induced deafness mutation in 1997, more than 150 GJB2 gene mutations have been found, of which 60% are autosomal recessive inheritance and 20% of the mutations are not clear to the hearing. According to different literature, the frequency of GJB2 mutation is of racial specificity. For example, the most common mutation in the Caucasian population is 35 delG, the Jewish population is 167 delT, and the most common mutation in the East Asian population is 235delC. The absolute number of sensorineural hearing loss in our country is over 80 million, accounting for 63% of the patients with deafness. The patients with 2-10% of the outpatients in our hospital were treated due to simple bilateral sensorineural hearing loss. In recent years, many centers in China have conducted screening of GJB2 gene mutation in the deaf-mute school, and also pointed out that 235delC is the most common deafness mutation of GJB2 in China. The detection rate is as high as 13% '21%, and the common polymorphism mutation (SNP) such as 79GA, and the controversial mutation such as 109 GA. However, the GGJB2 mutation screening, especially for patients with mild to moderate deafness, and the description of its deafness clinical features are not yet available for patients with outpatients with hearing loss, especially those with mild to moderate deafness. Therefore, screening is carried out in the patients with sensorineural hearing loss in our clinic, and the GJB2 gene mutation detection is extended to the patients with mild and moderate deafness from the patients with moderate and extremely severe deafness, It is of great significance to clinical and prenatal diagnosis and genetic counseling for deafness and to improve the epidemiological database of genetic deafness. Objective: To study the GJB2 gene mutation in the patients with sensorineural hearing loss and the hearing phenotype. Methods: A total of 233 sensorineural hearing-deaf patients and 85 direct-family members with a blood-related relationship were visited from May 29,2008 to March 25,2010, and the GJB2 gene coding region and the mitochondrial 12SrRNA process were performed in 100 patients with normal hearing. Results: Of the 233 patients,172 (73.8%) of the 233 patients were detected to change the GJB2 gene,57 cases (24.5%) of the 109 GA carriers, 17.4% of the allele frequency, and 25 (10) of the 235delC carriers. The frequency of allele was 6.9%.47 (20.2%) of 47 cases (20.2%) considered to be deaf to GJB2 gene mutation,5 (2.1%) considered to be deaf to the mitochondrial DNA The changes of GJB2 were detected and 17 new processes were detected. Among the pathogenic mutations of GJB2, 109GA (32 cases), accounting for 68.1% of GJB2-related deafness, including 24 cases of homozygous, 10.3% of the patients, and 51 of the patients with the GJB2-related deafness. 1%. The second was 235delC (18 cases), accounting for 38.3% of GJB2-related deafness patients and 7 cases of 235delC homozygosity, accounting for 14.9% of the patients with GJB2-related deafness, and 4 cases related to 299-300delAT, accounting for 8.5% of the patients with GJB2-related deafness, including 299-300delAT pure. In 1 case,15 cases were detected in the patient group, including 109 GA/235 delC 4 cases,109 GA/299-300delAT 1 case,109 GA/ 427CT 2 cases, 235delC/299-300delAT 3 cases, 176dell6/ 235delC, 235delC/ 504insAACG, 235delC/ 605ins46, 235delC/ 257C.G, 79GA, 109GA/ 478GA One case was found.109 GA homozygous mutation or 109-GA-containing compound heterozygous mutation was found in the patient's relative group and the normal control group, and only 109 GA heterozygous mutations were found (15 cases). 6 cases). The mitochondrial DNA pathogenic mutation included 1555AG3, 1494CT1 and 1519insC. Conclusion:1. GJB2109GA is the most common pathogenic mutation in the patients with sensorineural hearing loss, and it is a recessive form of autosomal recessive. The second and the third are 235delC,299-300delA, respectively. T.2. The characteristic of the disease: the onset age of the 235delC homozygote is earlier, and 85.7% is more severe, 42.9% is the most severe hearing loss before the birth to the age of 5, the hearing curve 57.1% is of the flat type, the incidence age of the 109 GA homozygote is slightly late, the age of 5 to 47 years old, and the like, There were distribution, mild condition, 95.8% of mild to moderate hearing loss, 87.5% of the hearing curve was down type, 3.79 GA + 341 AG was the change of the polymorphism Varied.4. It is considered that the mutation of 257CG and 478GA is a pathogenic mutation; the mutation property of 368CA is not clear; the newly discovered mutation sites 65AC, 88AG, 380GT and 494GA are all heterozygous mutations, and its function is still
【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2010
【分类号】：R764
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