中國(guó)散發(fā)感音神經(jīng)性聾患者GJB2基因突變的篩查分析
發(fā)布時(shí)間：2019-06-30 21:31
【摘要】： 感音神經(jīng)性聾是人類最常見的先天性疾患之一,也是耳科門診最常見的疾患之一,由遺傳、老化、耳毒性藥物、感染及噪聲等多因素共同作用而形成。據(jù)文獻(xiàn)報(bào)道,新生兒的耳聾發(fā)病率高達(dá)1-3/1000；在先天性耳聾中,有50%是由于遺傳因素引起的,其中70-80%是常染色體隱性遺傳,而50%的常染色體隱性遺傳性耳聾是與GJB2基因突變有關(guān)。自1997年第一個(gè)GJB2致耳聾突變被報(bào)道以來,已經(jīng)發(fā)現(xiàn)超過150個(gè)GJB2基因突變,其中,60%是常染色體隱性遺傳,20%的突變對(duì)聽力的影響不明確。據(jù)不同文獻(xiàn)報(bào)道,GJB2突變的頻率有種族特異性。例如,高加索人群最常見突變?yōu)?5delG,猶太人群為167delT,而東亞人群最常見突變?yōu)?35delC。我國(guó)的感音神經(jīng)性聾患者絕對(duì)數(shù)量超過8千萬,占耳聾患者的63%。我院耳科門診有可達(dá)2-10%的患者是由于單純雙側(cè)感音神經(jīng)性聾而就診。近幾年來,我國(guó)多個(gè)中心均展開了在聾啞學(xué)校為主的對(duì)GJB2基因突變的篩查,也指出了235delC為我國(guó)最常見的GJB2致聾突變,檢出率高達(dá)13%'21%,常見的多態(tài)性突變(SNP)如79GA,有爭(zhēng)議的突變?nèi)?09GA。但是針對(duì)散發(fā)的門診耳聾患者,尤其是對(duì)輕到中度耳聾患者的GJB2突變篩查,以及其致聾臨床特征的描述尚比較缺乏。因此,在我國(guó)門診散發(fā)感音神經(jīng)性聾患者中開展篩查,將GJB2基因突變檢測(cè)從中度、極重度聾患者推廣到輕、中度聾患者,將對(duì)耳聾的臨床及產(chǎn)前診斷和遺傳咨詢以及完善遺傳性耳聾的流行病學(xué)數(shù)據(jù)庫(kù)有重要意義。 目的：了解門診散發(fā)感音神經(jīng)性聾患者的GJB2基因突變情況以及與聽力表型的關(guān)系。方法：對(duì)2008年5月29日到2010年3月25日來我院耳科門診就診的233名感音神經(jīng)性聾患者及其85名有血緣關(guān)系的直系親屬,以及100名聽力正常的志愿者進(jìn)行GJB2基因編碼區(qū)和線粒體12 SrRNA突變篩查。結(jié)果：233名患者中,172名(73.8%)檢測(cè)到GJB2基因序列改變,109GA攜帶者57例(24.5%),等位基因頻率17.4%; 235delC攜帶者25例(10.7%),等位基因頻率6.9%。47例(20.2%)考慮為GJB2基因突變致聾,5例(2.1%)考慮與線粒體DNA致聾突變有關(guān)。檢出GJB2序列改變17種,新突變4種。在GJB2致病突變中,最常見的是109GA(32例),占GJB2相關(guān)性耳聾患者的68.1%,包括純合24例,占患者的10.3%,占GJB2相關(guān)性耳聾患者的51.1%。其次為235delC(18例),占GJB2相關(guān)性耳聾患者的38.3%, 235delC純合突變7例,只占患者的3%,占GJB2相關(guān)性耳聾患者的14.9%。299-300delAT相關(guān)的病例4例,占GJB2相關(guān)性耳聾患者的8.5%,包括299-300delAT純合1例。患者組檢出復(fù)合雜合致病突變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。在患者親屬組及正常對(duì)照組均未發(fā)現(xiàn)109GA純合突變或含109GA的復(fù)合雜合致病突變,只發(fā)現(xiàn)109GA雜合突變(15例和6例)。線粒體DNA致病突變包括1555AG3例,1494CT1例,1519insCA 1例。結(jié)論：1.GJB2109GA是散發(fā)感音神經(jīng)性聾患者的最常見的致病突變,并以常染色體隱性形式遺傳致病。列第二、三位的分別為235delC,299-300delAT。2.發(fā)病特點(diǎn)：235delC純合患者的發(fā)病年齡較早,85.7%在出生到5歲之前,病情較重,42.9%為重到極重度聽力損失,聽力曲線57.1%為平坦型；109GA純合子患者發(fā)病年齡稍晚,從5到47歲不等,在各年齡段均有分布,病情較輕,95.8%為輕到中度聽力損失,聽力曲線87.5%為下降型。3.79GA+341AG是多態(tài)性改變。4.認(rèn)為257CG,478GA為致病突變；368CA突變性質(zhì)不明確；新發(fā)現(xiàn)的突變位點(diǎn)65AC,88AG,380GT,494GA各一例,均為雜合突變,其功能尚不明確。
[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
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2010
【分類號(hào)】：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
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2010
【分類號(hào)】：R764
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