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摘要: 目的 探讨GJB2基因致聋突变婴儿的基因型与听力表型。方法 研究对象为就诊的121例GJB2基因致聋突变婴儿。受试者均接受新生儿听力筛查并有明确结果；接受声导抗、多频稳态反应等听力学检测；接受晶芯九项遗传性聋基因芯片或GJB2基因全编码区检测，确诊为GJB2基因致聋突变者。总体分析GJB2基因致聋突变婴儿基因型与听力表型；根据突变位点类型将受试者分为2个组：T/T组(截断/截断突变，89例)，T/NT组(截断/非截断突变，32例)，分析2组新生儿听力筛查结果、听力程度、听力曲线类型和双耳听力表型对称/非对称性。结果 截断突变中检出率最高的位点为c.235delC(64.88%，157/242)，非截断突变中检出率最高的位点为c.109G>A(11.16%，27/242)。基因型T/T组以c.235delC/c.235delC纯合突变为主(38.84%，47/121)，T/NT组以c.235delC/c.109G>A复合杂合突变为主(18.18%，22/121)。121例受试者中，新生儿听力筛查未通过占81.82%(99/121)；T/T组听力筛查未通过占86.52%(77/89)，T/NT组听力筛查未通过占68.75%(22/32)，2组差异有统计学意义(P＜0.05)。听力程度：听力正常14.05%(17/121)，听力损失85.95%(104/121)，其中极重度、重度、中度和轻度分别为31.40%(38/121)，24.79%(30/121)，19.01%(23/121)和10.74%(13/121)。T/T组89例均确诊为听力损失，其中以重度和极重度听力损失为主，占65.17%(58/89)；T/NT组听力正常占53.13%(17/32)，听力损失以轻度、中度听力损失为主，占37.5%(12/32)，2组差异有统计学意义(P＜0.05)。104例(208耳)听力损失患儿中，听力曲线类型以平坦型为主(49.03%，102/208)；T/T组平坦型检出率最高(47.19%，84/178)，其次为其他(20.22%，36/178)；T/NT组平坦型检出率为60.00%(18/30)，其次为上升型(20.00%，6/30)，2组差异有统计学意义(P＜0.05)。双耳听力表型对称50例(48.07%)，非对称54例(51.93%)；T/T组双耳非对称占53.93%(48/89)，T/NT组双耳对称占60.00%(9/15)，2组差异无统计学意义(P>0.05)。结论 该研究中T/T组以c.235delC/c.235delC纯合突变为主，T/NT组以c.235delC/c.109G>A复合杂合突变为主。听力表型具有多样性，不同基因型的听力表型存在差异，T/T组多为双耳非对称的极重度听力损失，T/NT组多为双耳对称的轻中度听力损失，遗传咨询时，应特别关注不同基因型的听力学特点。Abstract: Objective The aim of this study is to explore the genotype and hearing phenotype of deaf infants with mutation of GJB2 gene.Method Subjects were 121 infants with GJB2 gene mutations who were treated in the Children's Hearing Diagnosis Center of Beijing Tongren hospital. All subjects were accepted to undertake the universal newborns hearing screening(UNHS) and series of objective audiometry, including auditory brainstem response, distortion product otoacoustic emission, auditory steady-state response and other audiological tests. All subjects were screened for nine pathogenic variants in four genes or all exons of the GJB2 gene, and then were diagnosed as infants with GJB2 gene mutations. Initially, analyzing their genotypes and hearing phenotypes generally. Then, the subjects were divided into two groups according to the genotypes: T/T group(truncated/truncated mutations, 89 cases) and T/NT group(truncated/non-truncated mutations, 32 cases). Chi-square test was used to analyze the results of UNHS, hearing degree, audiogram patterns and symmetry/asymmetry of binaural hearing phenotype. Eventually, analyzing the results of UNHS.Result The most common truncated mutation was c.235delC(64.88%, 157/242) and the most common non-truncated mutation was c.109G>A(11.16%, 27/242). The homozygous mutation of c.235delC/c.235delC was the dominant in T/T group(38.84%, 47/121), and the compound heterozygous mutation of c.235delC/c.109G>A was the dominant in T/NT group(18.18%, 22/121). 81.82%(99/121) of subjects failed in UNHS, including 74.38%(90/121) with bilateral reference, 7.44%(9/121) with a single pass. The refer rate of UNHS of group T/T and T/NT were 86.52%(77/89) and 68.75%, respectively. There was a statistically significant difference between the two groups(P < 0.05). 85.95%(104/121) of subjects were diagnosed as hearing loss and 14.05%(17/121) of subjects were diagnosed as normal hearing. The degree of hearing loss: profound, severe, moderate and mild were 31.40%(38/121), 19.01%(23/121), 24.79%(30/121) and 10.74%(13/121), respectively. There was no subjects with normal hearing in T/T group and individuals with severe and profound hearing loss accounted for the highest proportion(65.17%, 58/89), while in T/NT group, normal hearing accounted for 53.13%(17/32) and mild and moderate hearing loss accounted for the highest proportion(37.5%, 12/32). There was statistically significant difference between the two groups(P < 0.05). Of 104 patients(208 ears) with hearing loss, the audiogram patterns: flat, descending, ascending, residual, Valley and other types were 49.03%(102/208), 12.02%(25/208), 8.65%(18/208), 7.69%(16/204), 3.36%(7/204) and 19.23%(40/204), respectively. The two most common types in T/T group were flat(47.19%, 84/178) and other types(20.22%, 36/178), while in T/NT group were flat(60.00%, 18/30) and ascending(20.00%, 6/30). There was statistically significant difference between the two groups(P < 0.05). There were 50 cases(48.07%) with symmetrical hearing phenotype and 54 cases(51.93%) with asymmetrical hearing phenotype. Asymmetry was predominant in T/T group(53.93%, 48/89), and symmetry was predominant in T/NT group(60.00%, 9/15). There was no statistically significant difference between the two groups(P>0.05).Conclusion In this study, c.235delC/c.235delC homozygous mutation was dominant in T/T group and c.235delC/c.109G>A heterozygous mutation was dominant in T/NT Group. The hearing phenotypes in T/T group were mostly bilateral asymmetric severe hearing loss, and those in T/NT Group were bilateral symmetric mild to moderate hearing loss, special attention should be paid to the audiological characteristics of different genotypes.
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Key words:
- GJB2 gene /
- infants /
- hearing loss /
- hearing loss /
- genotype /
- phenotype
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表 1 ASSR听反应阈与小儿行为测听听敏度校正因子
阈值/dB nHL 频率/kHz 0.5 1.0 2.0 4.0 20~25 15 10 5 15 30~35 10 10 5 10 40~45 10 5 5 10 50~55 10 5 5 10 60~65 5 5 0 5 70~75 5 5 0 5 80~85 5 0 0 5 90~95 0 0 0 0 100 0 0 0 0 注：eHL=nHL-校正因子；例如：ASSR测试500 Hz听反应阈为60 dB，则预估听力为60-5=55(dB eHL) 
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表 2 GJB2基因突变位点情况
突变类型 突变位点 检出方式 氨基酸改变 突变数量 突变频率/% T c.176del16 筛查 — 11 4.55 c.235delC 筛查 — 157 64.88 c.299delAT 筛查 — 42 17.36 NT c.109G>A 测序 Val37Ile 27 11.16 c.427C>T 测序 Arg143Trp 2 0.83 c.583A>G 测序 Met195Val 2 0.83 c.9G>A 测序 Trp3Ter 1 0.41
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表 3 2组基因型分布
组别 基因型 例数(%) T/T c.176dell6/c.176dell6 1(0.83) c.176del16/c.235delC 6(4.96) c.176del16/c.299delAT 1(0.83) c.235delC/c.235delC 47(38.84) c.235delC/c.299delAT 30(24.79) c.299delAT/c.299delAT 4(3.31) T/NT c.109G>A/c.176del16 2(1.65) c.109G>A/c.235delC 22(18.18) c.109G>A/c.299delAT 3(2.48) c.427C>T/c.235delC 2(1.65) c.538A>G/c.235delC 1(0.83) c.9G>A/c.235delC 2(1.65)
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表 4 2组新生儿听力筛查比较
例(%) 组别 双耳通过 单耳未通过 双耳未通过 χ2 P T/T组 12(13.48) 5(5.62) 72(80.90) 7.41 0.02 T/NT组 10(31.25) 4(12.50) 18(56.25)
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表 5 2组听力程度比较
例(%) 组别 例数 正常 轻度 中度 重度 极重度 χ2 P T/T组 89 0(0) 7(7.87) 24(26.97) 22(24.72) 36(40.46) 62.35 0.00 T/NT组 32 17(53.13) 6(18.75) 6(18.75) 1(3.12) 2(6.25)
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表 6 2组听力曲线类型比较
耳(%) 组别 例数 下降型 平坦型 谷型 上升型 残余型 其他 χ2 P T/T组 89 24(13.48) 84(47.19) 6(3.37) 12(6.74) 16(8.99) 36(20.22) 10.65 0.04 T/NT组 32 1(3.33) 18(60.00) 1(3.33) 6(20.00) 0(0) 4(13.33)
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表 7 2组听力表型对称/非对称性比较
例(%) 组别 例数 对称 非对称 χ2 P A型 B型 C型 T/T组 89 41(46.07) 17(19.10) 13(14.61) 18(20.22) 1.51 0.69 T/NT组 32 9(60.00) 1(6.67) 2(13.33) 3(20.00)
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| 引用本文: |
王现蕾, 赵雪雷, 黄丽辉, 等. GJB2基因致聋突变婴儿基因型与听力表型分析[J]. 临床耳鼻咽喉头颈外科杂志, 2020, 34(2): 113-118. doi: 10.13201/j.issn.1001-1781.2020.02.004
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| Citation: |
WANG Xianlei, ZHAO Xuelei, HUANG Lihui, et al. Analysis of genotypes and hearing phenotypes of mutation infants with deafness[J]. J Clin Otorhinolaryngol Head Neck Surg, 2020, 34(2): 113-118. doi: 10.13201/j.issn.1001-1781.2020.02.004
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