中国人群33104例单基因病携带者筛查的多中心研究  

Carrier screening for 223 monogenic diseases in Chinese population:a multi-center study in 33104 individuals

作　　者：侯伟[1] 付晓琳[1] 谢潇潇 张春燕[3] 边佳昕 毛翛 文娟[6] 罗春玉[7] 金华[8] 祝茜[9] 戚庆炜[10] 钱叶青[11] 袁静[12] 赵彦艳[13] 尹爱兰[14] 李树铁[15] 蒋宇林[10] 张蔓丽[3] 肖锐 卢彦平 Wei HOU;Xiaolin FU;Xiaoxiao XIE;Chunyan ZHANG;Jiaxin BIAN;Xiao MAO;Juan WEN;Chunyu LUO;Hua JIN;Qian ZHU;Qingwei QI;Yeqing QIAN;Jing YUAN;Yanyan ZHAO;Ailan YIN;Shutie LI;Yulin JIANG;Manli ZHANG;Rui XIAO;Yanping LU(Medical School of Chinese People's Liberation Army,Beijing 100853,China;Department of Gynecology and Obstetrics,First Medical Center of Chinese PLA General Hospital,Beijing 100853,China;Medical Innovation Research Division,Chinese PLA General Hospital,Beijing 100853,China;Zhejiang Biosan Biochemical Technologies Co.Ltd,Hangzhou 310058,China;Hunan Provincial Maternal and Child Health Care Hospital,Changsha 410008,China;Center for Medical Genetics,Hunan Key Laboratory of Medical Genetics,School of Life Sciences,Central South University,Changsha 410083,China;Center for Medical Genetics,Women's Hospital of Nanjing Medical University,Nanjing Maternity and Child Health Care Hospital,Nanjing 210011,China;Department of Obstetrics and Gynecology,Jinan Maternity and Child Care Hospital,Jinan 250000,China;Department of Medical Genetics,West China Second University Hospital,Sichuan University,Chengdu 610041,China;Department of Obstetrics and Gynecology,Peking Union Medical College Hospital,Peking Union Medical College&Chinese Academy of Medical Sciences,Beijing 100730,China;Department of Reproductive Genetics,Women's Hospital,School of Medicine Zhejiang University,Hangzhou 311215,China;Center for Prenatal Diagnosis,First Affiliated Hospital of Anhui Medical University,Hefei 230022,China;Department of Clinical Genetics,Shengjing Hospital of China Medical University,Shenyang 110004,China;Department of Gynecology and Obstetrics,Nanfang Hospital of Southern Medical University,Guangzhou 510515,China;Office of Standardized Training of Residents,First Affiliated Hospital of Hebei North University,Zhangjiakou 075061,China;Department of Gynecology and Obstetrics,Seventh Medical Center of PLA General Hospital,Beijing 100010,China)

机构地区：[1]中国人民解放军医学院,北京100853 [2]中国人民解放军总医院第一医学中心妇产科,北京100853 [3]中国人民解放军总医院医学创新研究部,北京100853 [4]浙江博圣生物技术股份有限公司,浙江杭州310058 [5]湖南省妇幼保健院,湖南长沙410008 [6]中南大学医学遗传学研究中心,湖南长沙410083 [7]南京市妇幼保健院遗传医学中心,江苏南京210011 [8]济南市妇幼保健院孕产医疗保健部,山东济南250000 [9]四川大学华西第二医院医学遗传科,四川成都610041 [10]中国医学科学院北京协和医院妇产科,北京100730 [11]浙江大学医学院附属妇产科医院生殖遗传科,浙江杭州311215 [12]安徽医科大学第一附属医院产前诊断中心,安徽合肥230022 [13]中国医科大学附属盛京医院临床遗传科,辽宁沈阳110004 [14]南方医科大学南方医院妇产科,广东广州510515 [15]河北北方学院附属第一医院住培办,河北张家口075061 [16]中国人民解放军总医院第七医学中心妇产医学部,北京100010

出　　处：《南方医科大学学报》2024年第6期1015-1023,共9页Journal of Southern Medical University

基　　金：国家重点研发计划(2021YFC1005303);军队后勤科研项目计划生育专项课题(23JSZ17)。

摘　　要：目的 通过大规模多中心的多种遗传病携带者筛查,调查中国人群单基因病的流行病学特征以及突变谱,为制定适合中国人群的遗传病预防策略提供依据。方法 本研究在中国的12个临床中心共招募33 104例受检者(16 610例女性),基于高通量测序和多种PCR对223个基因的携带者状态进行检测。结果 197个常染色体基因的合并携带者频率为55.58%,26个X连锁基因的合并携带者频率为1.84%。在16 669例家系中,共检出874对(5.24%)高危夫妇。其中常染色体基因高危夫妇584对(3.50%),X连锁基因高危夫妇306对(1.84%),16对夫妇同时为常染色体基因和X连锁基因高危夫妇。最常检出的常染色体高危基因包括GJB2(常染色体隐性耳聋1A,393对),HBA1/HBA2(α-地中海贫血,36对)和PAH(苯丙酮尿症,14对),SMN1(脊髓性肌萎缩症,14对)。最常检出的X连锁高危基因包括G6PD(G6PD缺乏症,236对),DMD(进行性假肥大性肌营养不良,23对)和FMR1(脆性X综合征,17对)。除外G6PD后的高危夫妇率为3.91%(651/16 669),进一步除外GJB2 c.109G>A位点后,高危夫妇率为1.72%(287/16 669)。理论上严重的单基因病出生缺陷的发病率约为4.35‰(72.5/16 669)。对导致高危夫妇最多的22个基因进行筛查可检出95%以上的高危夫妇,对导致高危夫妇最多的54个基因进行筛查可检出99%以上的高危夫妇。结论 本研究揭示了我国人群中223种单基因病的携带者频率,为中国人群的携带者筛查策略制定和panel设计提供依据。在携带者筛查实践中,针对某些特殊基因或变异位点的遗传咨询可能会面临困难。这些特殊基因或变异需要在检测前告知受检夫妇,并在可能的情况下提供不筛查这些基因或变异的选择。Objective To investigate the epidemiological characteristics and mutation spectrum of monogenic diseases in Chinese population through a large-scale,multicenter carrier screening.Methods This study was conducted among a total of 33104 participants(16610 females)from 12 clinical centers across China.Carrier status for 223 genes was analyzed using high-throughput sequencing and different PCR methods.Results The overall combined carrier frequency was 55.58%for 197 autosomal genes and 1.84%for 26 X-linked genes in these participants.Among the 16669 families,874 at-risk couples(5.24%)were identified.Specifically,584 couples(3.50%)were at risk for autosomal genes,306(1.84%)for X-linked genes,and 16 for both autosomal and X-linked genes.The most frequently detected autosomal at-risk genes included GJB2(autosomal recessive deafness type 1A,393 couples),HBA1/HBA2(α-thalassemia,36 couples),PAH(phenylketonuria,14 couples),and SMN1(spinal muscular atrophy,14 couples).The most frequently detected X-linked at-risk genes were G6PD(G6PD deficiency,236 couples),DMD(Duchenne muscular dystrophy,23 couples),and FMR1(fragile X syndrome,17 couples).After excluding GJB2 c.109G>A,the detection rate of at-risk couples was 3.91%(651/16669),which was lowered to 1.72%(287/16669)after further excluding G6PD.The theoretical incidence rate of severe monogenic birth defects was approximately 4.35‰(72.5/16669).Screening for a battery of the top 22 most frequent genes in the at-risk couples could detect over 95%of at-risk couples,while screening for the top 54 genes further increased the detection rate to over 99%.Conclusion This study reveals the carrier frequencies of 223 monogenic genetic disorders in the Chinese population and provides evidence for carrier screening strategy development and panel design tailored to the Chinese population.In carrier testing,genetic counseling for specific genes or gene variants can be challenging,and the couples need to be informed of these difficulties before testing and provided with options for not scree

关 键 词：携带者筛查 单基因病 遗传咨询 

分 类 号：R596.2[医药卫生—内科学]