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摘要: 目的 分析北京市23项新生儿耳聋基因筛查的突变频谱，为遗传咨询及临床诊疗提供依据。方法 研究对象为2022年12月-2023年6月在首都医科大学附属北京同仁医院接受23项耳聋基因筛查的新生儿21 006例。23项耳聋基因筛查包括4个基因23个位点： GJB2 基因(c.35delG、c.176_191del16、c.235delC、c.299_300delAT、c.109G>A、c.257C>G、c.512insAACG、c.427C>T、c.35insG)、 SLC26A4 基因(c.919-2A>G、c.2168A>G、c.1174A>T、c.1226G>A、c.1229C>T、c.1975G>C、c.2027T>A、c.589G>A、c.1707+5G>A、c.917insG、c.281C>T)、线粒体 12SrRNA 基因(m.1555A>G、m.1494C>T)和 GJB3 基因(c.538C>T)。分析各基因位点的突变率及等位基因突变频率。结果 21 006例中，耳聋基因筛查未通过率11.516%(2 419/21 006)。4个基因中 GJB2 基因突变率最高，为9.097%(1 911/21 006)，其次分别为 SLC26A4 基因2.123%(446/21 006)、 GJB3 基因0.362%(76/21 006)及线粒体 12SrRNA 基因0.176%(37/21 006)。 GJB2 基因中，c.109G>A和c.235delC突变率最高，分别为6.579%(1 382/21 006)和1.795%(377/21 006)。 SLC26A4 基因中，c.919-2A>G和c.2168A>G突变率最高，分别为1.423%(299/21 006)和0.233%(49/21 006)。等位基因突变频率， GJB2 基因c.109G>A最高，为3.359%(1 411/42 012)，其次为 GJB2 基因c.235delC，0.897%(377/42 012)及 SLC26A4 基因c.919-2A>G，0.719%(302/42 012)。结论 北京市23项新生儿耳聋基因筛查提示， GJB2 基因c.109G>A突变率和等位基因突变频率最高，值得临床重视。本研究丰富了23项新生儿耳聋基因筛查突变频谱的流行病学资料，可为临床提供依据。Abstract: Objective To analyze the mutation spectrum of 23-site chip newborn deafness genetic screening in Beijing, and to provide basis for genetic counseling and clinical diagnosis and treatment.Methods The study included 21 006 babies born in Beijing from December 2022 to June 2023. All subjects underwent newborn deafness genetic screening in Beijing Tongren Hospital, covering 23 variants in 4 genes, the GJB2 gene(c.35delG, c.176_191del16, c.235delC, c.299_300delAT, c.109G>A, c.257C>G, c.512insAACG, c.427C>T, c.35insG), SLC26A4 gene(c.919-2A>G, c.2168A>G, c.1174A>T, c.1226G>A, c.1229C>T, c.1975G>C, c.2027T>A, c.589G>A, c.1707+5G>A, c.917insG, c.281C>T), Mt12SrRNA(m.1555A>G, m.1494C>T) and GJB3 gene(c.538C>T). The mutation detection rate and allele frequency were analyzed.Results The overall mutation detection rate was 11.516%(2 419/21 006), with the GJB2 gene being the most frequently involved at 9.097%(1 911/21 006), followed by the SLC26A4 gene at 2.123%(446/21 006), the GJB3 gene at 0.362%(76/21 006) and Mt12SrRNA at 0.176%(37/21 006). Among the GJB2 genes, c.109G>A and c.235delC mutation detection rates were the highest, with 6.579%(1 382/21 006) and 1.795%(377/21 006), respectively. Of the SLC26A4 genes, c.919-2A>G and c.2168A>G had the highest mutation rates of 1.423%(299/21 006) and 0.233%(49/21 106), respectively. Regarding the allele frequency, GJB2 c.109G>A was the most common variant with an allele frequency of 3.359%(1 411/42 012), followed by the GJB2 c.235delC at 0.897%(377/42 012) and the SLC26A4 c.919-2A>G at 0.719%(302/42 012).Conclusion 23-site chip newborn deafness genetic screening in Beijing showed that GJB2 c.109G>A mutation detection rate and allele frequency were the highest. This study has enriched the epidemiological data of 23-site chip genetic screening mutation profiles for neonatal deafness, which can provide evidence for clinical practice.
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Key words:
- newborn /
- deafness genes /
- mutation detection rate /
- allele frequency
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表 1 23项耳聋基因筛查突变者的基因型分布
突变类型 基因型 突变例数 基因型占比(n=21 006) 纯合突变 c.109G>A/c.109G>A 29 0.138 c.919-2A>G/c.919-2A>G 3 0.014 复合杂合突变 c.235delC/c.109G>A 11 0.052 c.299_300delAT/c.109G>A 6 0.029 c.235delC/c.109G>A/c.538C>T 1 0.005 c.235delC/c.109G>A/c.919-2A>G 1 0.005 c.235delC/c.176_191del16 1 0.005 c.235delC/c.35delG 1 0.005 c.109G>A/c.35insG 1 0.005 c.919-2A>G/c.281C>T 1 0.005 线粒体12SrRNA突变 m.1555A>G均质 28 0.133 m.1555A>G异质 5 0.024 c.109G>A/m.1555A>G均质 2 0.010 c.109G>A/m.1494C>T均质 1 0.005 c.2168A>G/m.1555A>G均质 1 0.005 单杂合突变 c.109G>A杂合 1300 6.189 c.235delC杂合 351 1.671 c.919-2A>G杂合 273 1.300 c.299_300delAT杂合 95 0.452 c.538C>T杂合 68 0.324 c.2168A>G杂合 41 0.195 c.176_191del16杂合 30 0.143 c.1229C>T杂合 20 0.095 c.1174A>T杂合 19 0.090 c.1975G>C杂合 15 0.071 c.512insAACG杂合 13 0.062 c.35insG 9 0.043 c.1226G>A杂合 9 0.043 c.2027T>A杂合 8 0.038 c.427C>T杂合 7 0.033 c.589G>A杂合 6 0.029 c.257C>G杂合 6 0.029 c.1707+5G>A杂合 5 0.024 c.281C>T杂合 4 0.019 c.35delG 2 0.010 c.917insG杂合 1 0.005 双基因杂合突变 c.109G>A/c.919-2A>G 14 0.067 c.235delC/c.919-2A>G 6 0.029 c.109G>A/c.538C>T 5 0.024 c.235delC/c.2168A>G 4 0.019 c.109G>A/c.2168A>G 3 0.014 c.109G>A/c.1174A>T 2 0.010 c.109G>A/c.1707+5G>A 2 0.010 c.109G>A/c.589G>A 1 0.005 c.299_300delAT/c.538C>T 1 0.005 c.299_300delAT/c.919-2A>G 1 0.005 c.2027T>A/c.538C>T 1 0.005 c.109G>A/c.1226G>A 1 0.005 c.109G>A/c.1975G>C 1 0.005 c.109G>A/c.2027T>A 1 0.005 c.235delC/c.2027T>A 1 0.005 c.512insAACG/c.1707+5G>A 1 0.005 合计 2 419 11.516 
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表 2 4个基因23个位点的突变率
基因 位点 位点突变/例(%) 基因突变/例(%) GJB2 c.109G>A 1 382(6.579) 1 911(9.097) c.235delC 377(1.795) c.299_300delAT 103(0.490) c.176_191del16 31(0.148) c.512insAACG 14(0.067) c.35insG 10(0.048) c.427C>T 7(0.033) c.257C>G 6(0.029) c.35delG 3(0.014) SLC26A4 c.919-2A>G 299(1.423) 446(2.123) c.2168A>G 49(0.233) c.1174A>T 21(0.100) c.1229C>T 20(0.095) c.1975G>C 16(0.076) c.2027T>A 11(0.052) c.1226G>A 10(0.048) c.1707+5G>A 8(0.038) c.589G>A 7(0.033) c.281C>T 5(0.024) c.917insG 1(0.005) GJB3 c.538C>T 76(0.362) 76(0.362) 线粒体 m.1555A>G 36(0.171) 37(0.176) 12SrRNA m.1494C>T 1(0.005)
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表 3 23个位点的等位基因突变频率
基因 位点 突变例数 杂合突变数 纯合突变数 等位基因突变数 等位基因突变频率/% GJB2 c.109G>A 1 382 1 353 29 1 411 3.359 c.235delC 377 377 0 377 0.897 c.299_300delAT 103 103 0 103 0.245 c.176_191del16 31 31 0 31 0.074 c.512insAACG 14 14 0 14 0.033 c.35insG 10 10 0 10 0.024 c.427C>T 7 7 0 7 0.017 c.257C>G 6 6 0 6 0.014 c.35delG 3 3 0 3 0.007 SLC26A4 c.919-2A>G 299 296 3 302 0.719 c.2168A>G 49 49 0 49 0.117 c.1174A>T 21 21 0 21 0.050 c.1229C>T 20 20 0 20 0.048 c.1975G>C 16 16 0 16 0.038 c.2027T>A 11 11 0 11 0.026 c.1226G>A 10 10 0 10 0.024 c.1707+5G>A 8 8 0 8 0.019 c.589G>A 7 7 0 7 0.017 c.281C>T 5 5 0 5 0.012 c.917insG 1 1 0 1 0.002 GJB3 c.538C>T 76 76 0 76 0.181 线粒体12SrRNA m.1555A>G 36 5 31 36 0.086 m.1494C>T 1 0 1 1 0.002
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