基因筛查技术在新生儿常见遗传病筛查中的应用  

Application of gene screening technology in screening common newborn genetic diseases

作　　者：郝虎[1] 周伟 石聪聪[3] 李思涛[1] 马艳梅[3] 古霞 熊慧[1] 刘冰清[1] 蔡尧[1] 柳国胜[4] 封志纯 肖昕[1] Hao Hu;Zhou Wei;Shi Congcong;Li Sitao;Ma Yanmei;Gu Xia;Xiong Hui;Liu Bingqing;Cai Yao;Liu Guo-sheng;Feng Zhichun;Xiao Xin(Department of Pediatrics,the Sixth Affiliated Hospital of Sun Yat-Sen University,Guangzhou 510655,China;Department of Neonatology,Guangzhou Women and Children′s Medical Center,Guangzhou 510623,China;Laboratory of Inborn Errors of Metabolism,the Sixth Affiliated Hospital of Sun Yat-Sen University,Guangzhou 510655,China;Department of Pediatrics,the First Affiliated Hospital of Jinan University,Guangzhou 510632,China;Department of Pediatrics,the Seventh Medical Center,Chinese People′s Liberation Army General Hospital,Beijing 100700,China)

机构地区：[1]中山大学附属第六医院儿科,广州510655 [2]广州市妇女儿童医疗中心新生儿科,广州510623 [3]中山大学附属第六医院遗传代谢病实验室,广州510655 [4]暨南大学附属第一医院儿科,广州510632 [5]中国人民解放军总医院第七医学中心儿科,北京100700

出　　处：《中华实用儿科临床杂志》2020年第22期1712-1717,共6页Chinese Journal of Applied Clinical Pediatrics

基　　金：广州市科技计划项目(201704020230,201604020154)。

摘　　要：目的运用基于目的基因捕获的高通量测序技术对新生儿进行常见遗传病基因检测,了解新生儿常见遗传病的发病率及相关基因致病变异的携带率和变异类型,探讨该技术在新生儿遗传病筛查中的应用价值。方法收集2019年6月至2020年4月广东地区出生的1793例新生儿足跟血,采用基于目的基因捕获的高通量测序技术对138个新生儿常见遗传病相关基因的外显子区域进行检测,变异致病性的解读基于《遗传变异分类标准与指南(2017)》,其中已知致病和可能致病纳入阳性变异,采用Sanger测序技术对阳性变异位点进行验证,并采用计数方法对检测结果进行分析。结果1793例新生儿中,男978例,女815例;共筛出阳性158例,阳性率为8.81%,检测出阳性病种11种。在阳性病种中,常染色体隐性耳聋1A型41例(2.29%),Gilbert综合征或Crigler-Najjar综合征40例(2.23%),葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症33例(1.84%),家族性高胆固醇血症19例(1.06%),钠牛磺胆酸共转运多肽缺陷病18例(1.00%),线粒体非综合征型耳聋2例(0.11%),Citrin缺乏症2例(0.11%),全羧化酶合成酶缺乏症、β-珠蛋白生成障碍性贫血、异染性脑白质营养不良各1例(各占0.06%)。972例携带1个或多个基因的阳性变异位点,共涉及85种疾病,其中携带率较高的疾病为Gilbert综合征或Crigler-Najjar综合征(359例,20.02%)、常染色体隐性耳聋1A型(302例,16.84%)和钠牛磺胆酸共转运多肽缺陷病(291例,16.22%),其高频变异位点为UGT1A1基因c.211G>A位点、GJB2基因c.109G>A位点和SLC10A1基因c.800C>T位点。结论广东地区新生儿常见遗传病为常染色体隐性耳聋1A型、Gilbert综合征或Crigler-Najjar综合征、G6PD缺乏症、家族性高胆固醇血症和钠牛磺胆酸共转运多肽缺陷病,且存在人群高频携带位点;探索性地对新生儿常见遗传病进行基因筛查,可为新生儿基因筛查的开展积累数据和经验。Objective To detect the genes of common genetic diseases in newborns with the high-throughput sequencing technology based on target gene capture,to study the incidence rate of such diseases,the carrying rate and variant types of pathogenic mutations related to such diseases,and to explore the application value of the high-throughput sequencing technology in screening genetic diseases of newborns.Methods The heel blood of 1793 newborns born in Guangdong province from June 2019 to April 2020 were collected,and the exon regions of 138 common genetic disease-related genes in neonates were detected using the high-throughput sequencing technology based on target gene capture.The pathogenicity of the mutations was interpreted according to the"Classification Criteria and Guidelines for Genetic Variation(2017)",in which known disease and probable disease were considered as positive mutations.The positive mutations were verified by Sanger sequencing technology,and the test results were analyzed with statistical methods.Results Among the 1793 newborns,978 were male and 815 were female.A total of 158 positive cases were screened(8.81%),and 11 positive diseases were detected.Among the positive diseases,there were 41 cases(2.29%)of autosomal recessive deafness type 1A,40 cases(2.23%)of Gilbert syndrome or Crigler-Najjar syndrome,and 33 cases(1.84%)of glucose-6-phosphate dehydrogenase deficiency(1.84%),19 cases(1.06%)of familial hypercho-lesterolemia,18 cases(1.00%)of sodium taurocholate cotransporter peptide deficiency disease,2 cases(0.11%)of mitochondrial non-syndromic deafness,2 cases(0.11%)of Citrin deficiency,1 case(0.06%)of holocarboxylase synthase deficiency,1 case(0.06%)ofβ-thalassemia and 1 case(0.06%)of metachromatic leukodystrophies.Of all studied cases,972 carried one or more positive mutations,involving 85 kinds of diseases in total.The diseases with a high carrying rate were Gilbert syndrome or Crigler-Najjar syndrome(359 cases,20.02%),autosomal recessive deafness type 1A(302 cases,16.84%),and sodium taurocholat

关 键 词：高通量测序技术 基因 新生儿筛查 遗传病 变异 

分 类 号：R722.1[医药卫生—儿科] R440[医药卫生—临床医学]