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Results of Neonatal Genetic Screening for Hearing Loss in Peking Union Medical College Hospital in the Past 10 Years
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摘要:
目的 北京市启动新生儿耳聋基因筛查公益项目已10年, 本研究对北京协和医院实施该项目的筛查结果进行分析, 旨在为推动新生儿耳聋基因筛查项目高质量发展提供参考。 方法 回顾性收集新生儿耳聋基因筛查数据库中2012年4月至2022年3月于北京协和医院采用微阵列芯片法行耳聋基因筛查的新生儿筛查数据, 并结合北京协和医院耳聋遗传咨询门诊相关资料, 重点分析耳聋基因筛查未通过新生儿的基因突变位点、突变类型、遗传门诊就诊以及随访干预情况。 结果 共纳入行耳聋基因筛查新生儿165 813例, 其中筛查未通过8019例, 筛查阳性率为4.84%。新生儿群体中, 4种耳聋易感基因突变携带率由高至低排序依次为GJB2(2.52%, 4173/165 813)、SLC26A4(1.82%, 3016/165 813)、GJB3(0.34%, 570/165 813)、线粒体12S rRNA(0.24%, 405/165 813)。筛查发现多重突变携带者126例, 随访时听力均正常, 未予以特殊干预; 发现存在遗传性耳聋基因型(药物敏感性耳聋除外)44例, 均根据听力损失程度, 给予不同的干预手段; 发现存在药物敏感性耳聋基因型405例, 均通过药物警示卡片对新生儿及其母系家族成员进行用药警示。耳聋基因筛查新生儿的总体失访率为0.12%(204/165 813), 筛查未通过新生儿的总体遗传门诊就诊率为46.10%(3697/8019);其中第一阶段(2012年4月至2013年3月)、第二阶段(2013年4月至2017年12月)、第三阶段(2018年1月至2022年3月)的总体失访率分别为0.63%(72/11 489)、0.10%(80/81 663)、0.07%(52/72 661), 遗传门诊就诊率分别为38.05%(207/544)、39.44%(1496/3793)、54.16%(1994/3682)。Cochran-Armitage趋势性检验显示, 3个阶段的总体失访率逐渐越低, 就诊率逐渐升高(P均＜0.001)。 结论 新生儿耳聋基因筛查项目启动10年来, 北京协和医院逐步建立了成熟的筛查、追访和咨询干预平台, 该平台可对存在听力损失和听力障碍风险的新生儿及家族成员进行全方位早期预警、诊断以及干预。 Abstract:Objective To explore the operation status and effect of the neonatal deafness gene screeningin Beijing Union Medical College Hospital for the past 10 years and analyze the follow-up, genetic consultation and intervention to improve the quality of neonatal deafness gene screening. Methods From April 2012 to March 2022, the screening data of newborns with deafness genetic screening by microarray microarray in Peking Union Medical College Hospital, and the data from the genetic counseling clinic of Peking Union Medical College Hospital were retrospectively collected. The mutation loci, mutation types, genetic clinic visits and follow-up interventions of newborns who did not pass the deafness genetic screening were analyzed. Results Among 165 813 newborns, 8019 samples "failed" in the screening, accounting for 4.84%. Of the "failed" samples, 4173 cases carried GJB2 gene mutation, with a carrying rate of 2.52%; 3016 cases carried SLC26A4 gene mutation, with a carrying rate of 1.82%;570 cases carried GJB3 gene mutation, with a carrying rate of 0.34%; 405 cases carried homogeneous or heterogeneous mutation in 12S rRNA, with a carrying rate of 0.24%. During the screening, multiple mutation carriers were identified in 126 cases, all of whom had normal hearing at follow-up and were not given special intervention; 44 cases of deafness causing genotypes (except those at risk of drug-induced hearing loss), all of whom were given different interventions according to the degree of hearing loss; the presence of drug-sensitive deafness genotype was found in 405 cases, all of which were warned by drug warning cards for newborns and their maternal family members about drug use. The overall lost follow-up rate was 0.12%(204/165 813), and the overall genetic counselling rate of newborns who failed the screening was 46.10%(3697/8019). Among them, the lost rate of the first stage (from April 2012 to March 2013), the second stage (from April 2013 to December 2017) and the third stage (from January 2018 to March 2022) were 0.63%(72/11 489), 0.10%(80/81 663) and 0.07%(52/72 661), respectively. The visiting rate of genetic clinic was 38.05%(207/544), 39.44% (1496/3793) and 54.16%(1994/3682), respectively. The Cochran-Armitage trend test showed that the lost rate progressively lowered and the visiting rate gradually increased in the 3 stages (all P < 0.001). Conclusion In the past 10 years, a thorough screening, follow-up, consultation and intervention platform has been established, which can help us in the early warning, early diagnosis and early intervention of families and individuals at risk of hearing impairment. -
Key words:
- deafness gene /
- screening /
- neonatal /
- Peking Union Medical College Hospital
作者贡献：高儒真负责资料收集、论文撰写；樊悦、杨腾裕、历东东负责资料收集及文献检索；姜鸿、徐英春负责对稿件进行审核；陈晓巍负责确定主题及修订论文。利益冲突：所有作者均声明不存在利益冲突 -
表 1 2012—2022年北京协和医院新生儿耳聋基因筛查结果
时间(年) 筛查总数(n) 突变阳性(n) 筛查阳性率(%，95% CI) 2012 11 489 540 4.73(4.35~5.10) 2013 14 966 730 4.98(4.56~5.23) 2014 18 863 821 4.36(4.06~4.64) 2015 12 290 581 4.73(4.39~5.12) 2016 19 179 892 4.65(4.34~4.96) 2017 15 293 698 4.56(4.22~4.90) 2018 12 973 691 5.33(4.96~5.73) 2019 19 390 962 4.96(4.65~5.28) 2020 19 093 967 5.06(4.75~5.39) 2021 18 400 940 5.11(4.78~5.43) 2022 3877 197 5.08(4.38~5.78) 合计 165 813 8019 4.84(4.73~4.94) 
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表 2 2012—2022年北京协和医院165 813例新生儿4种常见耳聋易感基因突变携带情况
易感基因 相关疾病 突变位点 检出例数(n) 基因突变携带率(%，95%CI) GJB2 先天性感音神经性耳聋 c.35 del G 30 0.02(0.01~0.02) c.176 del 16 212 0.13(0.11~0.15) c.235 del C 3100 1.87(1.81~1.94) c.299 del AT 831 0.50(0.47~0.54) SLC26A4 大前庭导水管综合征 c.2168 A＞G 450 0.27(0.25~0.30) c.919-2 A＞G 2242 1.35(1.30~1.41) c.1174 A＞T* 48 0.03(0.02~0.04) c.1226 G＞A* 39 0.02(0.02~0.03) c.1229 C＞T* 53 0.03(0.02~0.04) c.1975 G＞C* 112 0.07(0.06~0.08) c.2027 T＞A* 43 0.03(0.02~0.03) c.IVS15+5 G＞A* 29 0.02(0.01~0.02) GJB3 后天高频感音神经性耳聋 c.538 C＞T 570 0.34(0.32~0.37) 线粒体12S rRNA 药物敏感性耳聋 m.1494 C＞T 25 0.02(0.01~0.02) m.1555 A＞G 380 0.23(0.21~0.25) 复合杂合、同时携带多个基因多个位点突变重复计算；*2018年新增筛查位点
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表 3 2012—2022年北京协和医院165 813例新生儿4种常见耳聋易感基因多重突变携带情况
基因型 检出例数(n) 听力筛查结果 随访干预手段 GJB2 c.235 del C杂合突变/GJB3 c.538 C＞T杂合突变 12 通过 随访听力正常，无特殊干预 GJB2 c.235 del C杂合突变/SLC26A4 c.2168 A＞G杂合突变 10 通过 随访听力正常，无特殊干预 GJB2 c.235 del C杂合突变/SLC26A4 c.919-2 A＞G杂合突变 49 5例未通过，44例通过 随访听力正常，无特殊干预 GJB2 c.235 del C杂合突变/SLC26A4 c.1975 G＞C杂合突变* 2 通过 随访听力正常，无特殊干预 GJB2 c.235 del C杂合突变/12S rRNA m.1494 C＞T均质/异质突变 2 通过 随访听力正常，无特殊干预 GJB2 c.235 del C杂合突变/12S rRNA m.1555 A＞G均质/异质突变 12 通过 随访听力正常，无特殊干预 GJB2 c.299 del AT杂合突变/GJB3 c.538 C＞T杂合突变 2 通过 随访听力正常，无特殊干预 GJB2 c.299 del AT杂合突变/SLC26A4 c.2168 A＞G杂合突变 1 通过 随访听力正常，无特殊干预 GJB2 c.299 del AT杂合突变/SLC26A4 c.919-2 A＞G杂合突变 7 通过 随访听力正常，无特殊干预 GJB2 c.299 del AT杂合突变/12S rRNA m.1494 C＞T均质/异质突变 1 通过 随访听力正常，无特殊干预 GJB2 c.299 del AT杂合突变/SLC26A4 c.1174 A＞T杂合突变* 1 通过 随访听力正常，无特殊干预 GJB2 c.299 del AT杂合突变/SLC26A4 c.1226 G＞A杂合突变* 1 通过 随访听力正常，无特殊干预 GJB2 c.299 del AT杂合突变/SLC26A4 c.1975 G＞C杂合突变* 1 通过 随访听力正常，无特殊干预 GJB2 c.176 del 16杂合突变/SLC26A4 c.919-2 A＞G杂合突变 2 通过 随访听力正常，无特殊干预 GJB3 c.538 C＞T杂合突变/SLC26A4 c.919-2 A＞G杂合突变 11 通过 随访听力正常，无特殊干预 GJB3 c.538 C＞T杂合突变/SLC26A4 c.2168 A＞G杂合突变 2 通过 随访听力正常，无特殊干预 GJB3 c.538 C＞T杂合突变/SLC26A4 c.1174 A＞T杂合突变* 1 通过 随访听力正常，无特殊干预 GJB3 c.538 C＞T杂合突变/12S rRNA m.1555 A＞G均质/异质突变 1 通过 随访听力正常，无特殊干预 SLC26A4 c.2168 A＞G杂合突变/12S rRNA m.1555 A＞G均质/异质突变 1 通过 随访听力正常，无特殊干预 SLC26A4 c.IVS15+5 G＞A杂合突变*/12S rRNA m.1555 A＞G均质/异质突变 1 通过 随访听力正常，无特殊干预 SLC26A4 c.919-2 A＞G杂合突变/12S rRNA m.1555 A＞G均质/异质突变 6 通过 随访听力正常，无特殊干预 *2018年新增筛查位点
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表 4 2012—2022年北京协和医院存在致聋基因型新生儿听力筛查及随访干预情况
基因型 突变类型 检出例数(n) 听力筛查结果 随访干预手段 GJB2 c.176 del 16/GJB2 c.235 del C 复合杂合突变 3 未通过 建议助听器验配或人工耳蜗植入 GJB2 c.235 del C/GJB2 c.235 del C 纯合突变 18 2例通过，16例未通过 1例听力随访中，余建议助听器验配或人工耳蜗植入 GJB2 c.235 del C/GJB2 c.299 del AT 复合杂合突变 11 1例通过，10例未通过 建议助听器验配或人工耳蜗植入 GJB2 c.299 del AT/GJB2 c.299 del AT 纯合突变 1 未通过 建议助听器验配或人工耳蜗植入 SLC26A4 c.919-2 A＞G/SLC26A4 c.919-2 A＞G 纯合突变 7 3例通过，4例未通过 2例听力监测中，5例予以助听器验配或人工耳蜗植入, 指导避免听力损伤的诱发因素 SLC26A4 c.2168 A＞G/SLC26A4 c.IVS15+ 5 G＞A* 复合杂合突变 1 未通过 助听器验配，指导避免听力损伤的诱发因素 SLC26A4 c.2168 A＞G/SLC26A4 c.1229 C＞T* 复合杂合突变 1 未通过 助听器验配，指导避免听力损伤的诱发因素 SLC26A4 c.919-2 A＞G/SLC26A4 c.1226 G＞A* 复合杂合突变 1 未通过 助听器验配，指导避免听力损伤的诱发因素 SLC26A4 c.1229 C＞T/SLC26A4 c.1975 G＞C* 复合杂合突变 1 未通过 助听器验配，指导避免听力损伤的诱发因素 12S rRNA m.1494 C＞T 均质/异质突变 25 通过 母系家族成员药物警示，听力随访 12S rRNA m.1555 A＞G 均质/异质突变 380 通过 母系家族成员药物警示，听力随访 *2018年新增筛查位点
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