湖北某特殊学校52例耳聋患儿耳聋基因检测结果分析
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摘要
目的对某特殊学校耳聋患者进行聋病易感基因GJB2、GJB3、SLC26A4和线粒体DNA4(mtDNA)个基因13个位点的筛查,并与该地区正常儿童进行比对,了解其突变基因与位点。方法 2017年3-9月采集52例耳聋患儿与1 131例正常儿童的外周血,提取基因组DNA,应用遗传性耳聋基因芯片检测试剂盒对GJB2、SLC26A4、mtDNA及GJB3基因的13个突变位点进行检测。结果 52例耳聋学生中18例(34.63%)突变携带者,携带不同突变基因。GJB2基因突变13例(25.00%),其中纯合突变3例(5.77%),单杂合突变6例(11.54%),复合杂合突变4例(7.69%)。SLC26A4基因突变3例(5.77%),其中纯合突变2例(3.85%),单杂合突变1例(1.92%);mtDNA基因突变2例(3.85%),均为1555A>G均质突变;未检测到GJB3基因突变。而1 131例正常儿童中125例(11.05%)突变携带者,携带不同突变基因。GJB2基因突变79例(6.99%),SLC26A4基因突变35例(3.09%),mtDNA基因突变11例(0.97%),未检测到GJB3基因突变。耳聋患儿与正常儿童耳聋基因检测分布差异有统计学意义(χ2=25.98,P<0.001)。结论该聋哑学校耳聋突变热点基因以GJB2和SLC26A4为主,且GJB2 235delC(19.23%)是最常见突变位点,耳聋基因检测为减少出生缺陷提供了依据。
Objectives To screen 13 sites of the genes GJB2,GJB3,SLC26 A4 and mitochondrial DNA(mtDNA)susceptible to deafness in deaf children from a special school,and to compare with hearing normal children,in order to know about the mutation gene and sites. Methods The peripheral blood of 52 deaf children and 1 131 children with normal hearing were collected,and genomic DNA was extracted from March to September 2017.And 13 mutation sites of GJB2,SLC26 A4,mtDNAand GJB3 genes were detected by using the hereditary deafness gene chip detection kit. Results Totally 18(34.63%)mutation carriers were detected in 52 deaf patients who carried different mutation genes.And 13 cases with GJB2 gene mutations(25.00%),including 3(5.77%)cases of homozygous mutation,6(11.54%)cases of single heterozygous mutation and 4(7.69%)cases of complex heterozygous mutation.Also,3(5.77%)cases with SLC26 A4 gene mutations,including 2(3.85%)cases of homozygous mutation and 1(1.92%)cases of single heterozygous mutation.And2 cases with mtDNAgene mutations(3.85%),which were 1555 A>G homogenous mutations.No GJB3 gene mutation was detected.Finally 125(11.05%)mutation carriers were detected carrying different mutated genes in 1 131 children with normal hearing,of whom 79(6.99%)cases with GJB2 gene mutations,35(3.09%)cases with SLC26 A4 gene mutations,11 cases with mtDNAgene mutations(0.97%).No GJB3 gene mutation was detected.There were significant differences on gene distribution between deaf children and normal children(χ2=25.98,P<0.001). Conclusions The hotspot gene of deafness mutation mainly are GJB2 and SLC26 A4 in this special school,and GJB2 235 delC(19.23%)is the most common mutation site.And genetic testing of deafness provides evidence for reducing birth defects.
Objectives To screen 13 sites of the genes GJB2,GJB3,SLC26 A4 and mitochondrial DNA(mtDNA)susceptible to deafness in deaf children from a special school,and to compare with hearing normal children,in order to know about the mutation gene and sites. Methods The peripheral blood of 52 deaf children and 1 131 children with normal hearing were collected,and genomic DNA was extracted from March to September 2017.And 13 mutation sites of GJB2,SLC26 A4,mtDNAand GJB3 genes were detected by using the hereditary deafness gene chip detection kit. Results Totally 18(34.63%)mutation carriers were detected in 52 deaf patients who carried different mutation genes.And 13 cases with GJB2 gene mutations(25.00%),including 3(5.77%)cases of homozygous mutation,6(11.54%)cases of single heterozygous mutation and 4(7.69%)cases of complex heterozygous mutation.Also,3(5.77%)cases with SLC26 A4 gene mutations,including 2(3.85%)cases of homozygous mutation and 1(1.92%)cases of single heterozygous mutation.And2 cases with mtDNAgene mutations(3.85%),which were 1555 A>G homogenous mutations.No GJB3 gene mutation was detected.Finally 125(11.05%)mutation carriers were detected carrying different mutated genes in 1 131 children with normal hearing,of whom 79(6.99%)cases with GJB2 gene mutations,35(3.09%)cases with SLC26 A4 gene mutations,11 cases with mtDNAgene mutations(0.97%).No GJB3 gene mutation was detected.There were significant differences on gene distribution between deaf children and normal children(χ2=25.98,P<0.001). Conclusions The hotspot gene of deafness mutation mainly are GJB2 and SLC26 A4 in this special school,and GJB2 235 delC(19.23%)is the most common mutation site.And genetic testing of deafness provides evidence for reducing birth defects.
引文
[1] Fact sheet No.300on deafness and hearing loss[EB/OL].[2015-05-13]http://www.who.int/mediacentre/factsheets/fs300/en/.
[2] Minarik G,Tretinarova D,Szemes T,et al.Prevalence of DFNB1 mutations in Slovak patients with non-syndromic hearing loss[J].Int J Pediatr Otorhinolaryngol,2012,76(3):400-403.
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[5] Du Y,Huang L,Wang X,et al.Clinical data analysis of genotypes and phenotypes of deafness gene mutations in newborns:a retrospective study[J].Biosci Trends,2017,11(4):460-468.
[6] Wen XH,Hong Q,Yang K,et al.Analysis of the rate of common genetic mutations of deaf in pregnant women[J].J China Med Univ,2015,44(2):152-155.
[7]杜小云,刘郁明,唐凯,等.宝鸡地区非综合征性耳聋患者基因检测分析[J].中国优生与遗传杂志,2017,25(3):33-34.
[8]史敏,刘斐,胥亮,等.广西壮族自治区23个非综合征型耳聋家系分子遗传病因分析[J].临床耳鼻咽喉头颈外科杂志,2017,31(4):277-283.
[9]高薇薇,卢文翔,张雷,等.宁波地区非综合征型耳聋患儿耳聋基因热点突变筛查分析[J].浙江医学,2017,39(12):957-960.
[10] Meena R,Ayub M.Genetics of human hereditary hearing impairment[J].J Ayub Med Coll Abbottabad,2017,29(4):671-676.
[11] García IE,Bosen F,Mujica P,et al.From hyperactive connexin26hemichannels to impairments in epidermal calcium gradient and permeability barrier in the keratitis-ichthyosisdeafness syndrome[J].J Invest Dermatol,2016,136(3):574-583.
[12] Riahi Z,Hammami H,Ouragini H,et al.Update of the spectrum of GJB2gene mutations in Tunisian families with autosomal recessive nonsyndromic hearing loss[J].Gene,2013,525(1):1-4.
[13] Bakhchane A,Bousfiha A,Charoute H,et al.Update of the spectrum of GJB2gene mutations in 152Moroccan families with autosomal recessive nonsyndromic hearing loss[J].Eur J Med Genet,2016,59(6-7):325-329.
[14] Yao J,Lu Y,Wei Q,et a1.A systematic review and metaanalysis of 235delC mutation of GJB2gene[J].J Transl Med,2012,10(1):136.
[15] Du Y,Huang L,Wang X,et al.Clinical data analysis of genotypes and phenotypes of deafness gene mutations in newborns:a retrospective study[J].Biosci Trends,2017,11(4):460-468.
[16] He X,Li X,Guo Y,et al.Newborn screening of genetic mutations in common deafness genes with bloodspot-based gene chip array[J].Am J Audiol,2018,27(1):57-66.
[17] Liang Y,Peng Q,Wang KW,et al.A novel mutation in the SLC26A4gene in a Chinese family with nonsyndromic hearing loss and enlarged vestibular aqueduct[J].Int J Pediatr Otorhinolaryngol,2018,107:97-100.
[18] Yao J,Qian X,Bao J,et al.Probing the effect of two heterozygous mutations in codon 723of SLC26A4on deafness phenotype based on molecular dynamics simulations[J].Sci Rep,2015,5:10831.
[19] Zhang F,Xiao Y,Xu L,et al.Mutation analysis of the common deafness genes in patients with nonsyndromic hearing loss inLinyi by SNP scan assay[J].Bio Med Res Int,2016,1302914.
[20] Shin JW,Lee SC,Lee HK,et al.Genetic screening of GJB2and SLC26A4in Korean cochlear implantees:experience of soree ear clinic[J].Clin Exp Otorhinolaryngol,2012,5(Suppl 1):10-13.
[21] Campbell C,Cucci RA,Prasad S,et al.Pendred syndrome,DFNB4,and PDS/SLC26A4identification of eight novel mutations and possible genotype-phenotype correlations[J].Hum Mutat,2001,17(5):403-411.
[22]张怡,张蕾,张丽娜.黑龙江某聋哑学校103例耳聋患者耳聋基因分析[J].中国优生与遗传杂志,2016,24(11):101-103.
[23] Hobbie SN,Akshay S,Kalapala SK,et al.Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity[J].Proc Natl Acad Sci U.S.A,2008,105(52):20888-20893.
[24] Estivill X,Govea N,Barcelo E,et al.Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides[J].Am J Hum Genet,1998,62(1):27-35.
[25] Oh SK,Choi SY,Yu SH,et al.Evaluation of the pathogenicity of GJB3and GJB6variants associated with nonsyndromic hearing loss[J].Biochim Biophys Acta,2013,1832(1):285-291.
[26] Liang Y,Wang K,Peng Q,et al.A novel variant in the CDH23gene is associated with non-syndromic hearing loss in a Chinese family[J].Int J Pediatr Otorhinolaryngol,2018,104:108-112.
[27] Chang MY,Lee C,Han JH,et al.Expansion of phenotypic spectrum of MYO15Apathogenic variants to include postlingual onset of progressive partial deafness[J].BMC Med Genet,2018,19(1):29.
[2] Minarik G,Tretinarova D,Szemes T,et al.Prevalence of DFNB1 mutations in Slovak patients with non-syndromic hearing loss[J].Int J Pediatr Otorhinolaryngol,2012,76(3):400-403.
[3] Nance WE,Lim BG,Dodson KM.Importance of congenital cytomegalovirus infections as a cause for pre-lingual hearing loss[J].J Clin Virol,2006,35(2):221-225.
[4] Morton CC,Nance WE.Newborn hearing screening-a silent revolution[J].N Engl J Med,2006,354(20):2151-2164.
[5] Du Y,Huang L,Wang X,et al.Clinical data analysis of genotypes and phenotypes of deafness gene mutations in newborns:a retrospective study[J].Biosci Trends,2017,11(4):460-468.
[6] Wen XH,Hong Q,Yang K,et al.Analysis of the rate of common genetic mutations of deaf in pregnant women[J].J China Med Univ,2015,44(2):152-155.
[7]杜小云,刘郁明,唐凯,等.宝鸡地区非综合征性耳聋患者基因检测分析[J].中国优生与遗传杂志,2017,25(3):33-34.
[8]史敏,刘斐,胥亮,等.广西壮族自治区23个非综合征型耳聋家系分子遗传病因分析[J].临床耳鼻咽喉头颈外科杂志,2017,31(4):277-283.
[9]高薇薇,卢文翔,张雷,等.宁波地区非综合征型耳聋患儿耳聋基因热点突变筛查分析[J].浙江医学,2017,39(12):957-960.
[10] Meena R,Ayub M.Genetics of human hereditary hearing impairment[J].J Ayub Med Coll Abbottabad,2017,29(4):671-676.
[11] García IE,Bosen F,Mujica P,et al.From hyperactive connexin26hemichannels to impairments in epidermal calcium gradient and permeability barrier in the keratitis-ichthyosisdeafness syndrome[J].J Invest Dermatol,2016,136(3):574-583.
[12] Riahi Z,Hammami H,Ouragini H,et al.Update of the spectrum of GJB2gene mutations in Tunisian families with autosomal recessive nonsyndromic hearing loss[J].Gene,2013,525(1):1-4.
[13] Bakhchane A,Bousfiha A,Charoute H,et al.Update of the spectrum of GJB2gene mutations in 152Moroccan families with autosomal recessive nonsyndromic hearing loss[J].Eur J Med Genet,2016,59(6-7):325-329.
[14] Yao J,Lu Y,Wei Q,et a1.A systematic review and metaanalysis of 235delC mutation of GJB2gene[J].J Transl Med,2012,10(1):136.
[15] Du Y,Huang L,Wang X,et al.Clinical data analysis of genotypes and phenotypes of deafness gene mutations in newborns:a retrospective study[J].Biosci Trends,2017,11(4):460-468.
[16] He X,Li X,Guo Y,et al.Newborn screening of genetic mutations in common deafness genes with bloodspot-based gene chip array[J].Am J Audiol,2018,27(1):57-66.
[17] Liang Y,Peng Q,Wang KW,et al.A novel mutation in the SLC26A4gene in a Chinese family with nonsyndromic hearing loss and enlarged vestibular aqueduct[J].Int J Pediatr Otorhinolaryngol,2018,107:97-100.
[18] Yao J,Qian X,Bao J,et al.Probing the effect of two heterozygous mutations in codon 723of SLC26A4on deafness phenotype based on molecular dynamics simulations[J].Sci Rep,2015,5:10831.
[19] Zhang F,Xiao Y,Xu L,et al.Mutation analysis of the common deafness genes in patients with nonsyndromic hearing loss inLinyi by SNP scan assay[J].Bio Med Res Int,2016,1302914.
[20] Shin JW,Lee SC,Lee HK,et al.Genetic screening of GJB2and SLC26A4in Korean cochlear implantees:experience of soree ear clinic[J].Clin Exp Otorhinolaryngol,2012,5(Suppl 1):10-13.
[21] Campbell C,Cucci RA,Prasad S,et al.Pendred syndrome,DFNB4,and PDS/SLC26A4identification of eight novel mutations and possible genotype-phenotype correlations[J].Hum Mutat,2001,17(5):403-411.
[22]张怡,张蕾,张丽娜.黑龙江某聋哑学校103例耳聋患者耳聋基因分析[J].中国优生与遗传杂志,2016,24(11):101-103.
[23] Hobbie SN,Akshay S,Kalapala SK,et al.Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity[J].Proc Natl Acad Sci U.S.A,2008,105(52):20888-20893.
[24] Estivill X,Govea N,Barcelo E,et al.Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides[J].Am J Hum Genet,1998,62(1):27-35.
[25] Oh SK,Choi SY,Yu SH,et al.Evaluation of the pathogenicity of GJB3and GJB6variants associated with nonsyndromic hearing loss[J].Biochim Biophys Acta,2013,1832(1):285-291.
[26] Liang Y,Wang K,Peng Q,et al.A novel variant in the CDH23gene is associated with non-syndromic hearing loss in a Chinese family[J].Int J Pediatr Otorhinolaryngol,2018,104:108-112.
[27] Chang MY,Lee C,Han JH,et al.Expansion of phenotypic spectrum of MYO15Apathogenic variants to include postlingual onset of progressive partial deafness[J].BMC Med Genet,2018,19(1):29.