54个眼皮肤白化病家系的基因变异分析与产前诊断  

Gene variation analysis and prenatal diagnosis for 54 families with oculocutaneous albinism

作　　者：张钏[1,2,3] 郝胜菊 孟照琰 杨兰 冯暄 张庆华 周秉博 王兴 惠玲 陈雪 郑雷 王琰 曹宗富 Zhang Chuan;Hao Shengju;Meng Zhaoyan;Yang Lan;Feng Xuan;Zhang Qinghua;Zhou Bingbo;Wang Xing;Hui Ling;Chen Xue;Zheng Lei;Wang Yan;Cao Zongfu(Medical Genetic Center,Gansu Province Maternal and Child Health Care Hospital,Lanzhou 730050,China;National Research Institute for Health and Family Planning,National Human Genetic Resources Center,Beijing 100081,China;Graduate School of Peking Union Medical College,Beijing 100730,China)

机构地区：[1]甘肃省妇幼保健院医学遗传中心,兰州730050 [2]国家卫生健康委科学技术研究所国家人类遗传资源中心,北京100081 [3]北京协和医学院研究生院,100730

出　　处：《中华围产医学杂志》2021年第6期417-422,共6页Chinese Journal of Perinatal Medicine

基　　金：国家"十三五"重点专项(2016YFC1000307);国家重点研发计划(2018YFC1002500);国家人口与生殖健康科学数据中心项目(2005DKA32408);甘肃省自然科学基金(18JR3RA036、1606RJZA159)。

摘　　要：目的探讨54个眼皮肤白化病(oculocutaneous albinism,OCA)家系致病基因位点及其产前基因诊断特点。方法回顾性纳入2014年5月至2020年5月在甘肃省妇幼保健院确诊为OCA的54例先证者及其家系,采用Sanger测序对先证者TYR基因进行直接测序,对Sanger测序未能明确变异的先证者采用高通量测序进行变异分析,并用Sanger测序在其父母中进行验证。16个家系的母亲再次妊娠,于孕18~21周抽取羊水15 ml,联合Sanger测序及短串联重复序列连锁分析方法进行产前基因诊断。采用描述性统计分析。结果54例OCA先证者经Sanger测序及高通量测序检测后,48例被诊断为OCA1型,5例被诊断为OCA2型,1例被诊断为OCA4型。在48例OCA1型先证者中共检测到26个变异位点,包括15种错义变异、5种无义变异、3种剪接变异、3种移码变异。其中,变异频率最高的是c.929insC(29%,28/96),其次为c.896G>A(11%,11/96)、c.832C>T(8%,8/96)和c.703T>C(5%,5/96)。16个产前诊断家系的16例胎儿均得到明确诊断,5例为患胎,均终止妊娠;7例杂合携带者和4例未检测到与先证者相同致病等位基因的胎儿孕妇均选择继续妊娠并分娩。16例胎儿短串联重复序列连锁分析均排除母源污染。11例孕妇分娩后1个月电话随访,新生儿表型均正常,与产前基因诊断结果相符。结论基因诊断技术可成功对OCA患者进行精准分型,并有助于对再生育家庭提供产前诊断及生育指导。Objective To investigate the pathogenic gene locus and prenatal genetic diagnosis of 54 families with oculocutaneous albinism(OCA).Methods This retrospective study enrolled 54 OCA probands and their families from Gansu Province Maternal and Child Health Care Hospital from May 2014 to May 2020.TYR gene variation screening was performed on the probands by Sanger sequencing.Those with negative results were analyzed by high-throughput sequencing,and further verification was performed on their parents by Sanger sequencing.Among the 54 families,15 ml amniotic fluid were collected from 16 women at 18-21 gestational weeks in their subsequent pregnancy.Sanger sequencing combined with short tandem repeats sequence for linkage analysis were performed for genetic analysis.All data were analyzed using descriptive statistical analysis.Results Out of the 54 OCA probands,48 were diagnosed as OCA1,five were OCA2 and one was OCA4 based on the Sanger sequencing and high-throughput sequencing detection.A total of 26 different variation sites were involved in the 48 OCA1 probands,including 15 missense mutations,five nonsense mutations,three splicing mutations,and three frame-shift mutations,among which,c.929insC(29%,28/96)was the most frequent mutation,followed by c.896G>A(11%,11/96),c.832C>T(8%,8/96)and c.703T>C(5%,5/96).The diagnosis was confirmed in all 16 fetuses in the 16 families that underwent prenatal diagnosis.Five of them were affected and their mothers chose to terminate the pregnancies,the other 11 pregnancies continued to delivery,including seven heterozygous carriers and four fetuses without the same pathogenic allele as the proband.Maternal contamination was excluded in all prenatal samples using short tandem repeat for linkage analysis.All 11 children were in good health during telephone follow-up one month after birth.Postnatal validations were consistent with the prenatal tests.Conclusions Genetic diagnosis could accurately identify various types of OCA and help to provide prenatal diagnosis and fertility consultati

关 键 词：白化病 眼皮肤 膜转运蛋白质类 突变 产前诊断 系谱 

分 类 号：R714.5[医药卫生—妇产科学]