全外显子组测序技术在先天性结构异常胎儿中的应用  

Application of whole exome sequencing technology in fetuses with congenital structural abnormalities

作　　者：黎璐珊 符芳[1] 李茹[1] 喻秋霞 王丹[1] 雷婷缨 邓琼 张雯雯 杜坤 杨昕[1] 韩瑾[1] 甄理[1] 潘敏[1] 张丽娜 黎福成 张永玲[1] 景象一 李东至[1] 廖灿[1] Li Lushan;Fu Fang;Li Ru;Yu Qiuxia;Wang Dan;Lei Tingying;Deng Qiong;Zhang Wenwen;Du Kun;Yang Xin;Han Jin;Zhen Li;Pan Min;Zhang Li’na;Li Fucheng;Zhang Yongling;Jing Xiangyi;Li Dongzhi;Liao Can(Prenatal Diagnostic Center,Guangzhou Women and Children’s Medical Center,Guangzhou Medical University,Guangzhou,Guangdong 510623 China)

机构地区：[1]广州医科大学附属广州市妇女儿童医疗中心产前诊断中心,510623

出　　处：《中华医学遗传学杂志》2021年第9期900-906,共7页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金(81671474,81771594,81873836);广东省科技厅项目(2017A030313460,2019A1515012034)。

摘　　要：目的探讨全外显子组测序技术在先天性结构异常胎儿产前诊断中的应用价值。方法对排除了染色体病及基因组不平衡的1147个先天性结构异常胎儿家系进行全外显子组测序分析。根据随访结果,对初次测序分析并未明确诊断但孕晚期或出生后有新增表型胎儿的数据进行重新分析。根据累及器官的数目及部位分组。采用STRING数据库以及Cytoscape软件绘制所有的致病性/可能致病性变异的基因调控网络图。应用Fisher确切概率法对各组致病基因诊断率的差异进行比较。结果共有160例胎儿获得了阳性诊断,其中包含数据重分析检出的8例(4.9%,8/163),共涉及125个致病基因的178个变异位点,总体阳性诊断率为13.9%。诊断率最高和最低的分别为骨骼畸形组(31.5%,39/124)以及胸部畸形组(0,0/32)。胎儿水肿及胎儿宫内生长受限的致病基因簇均独立分布,且与主要结构畸形的致病基因无关。每对父母携带相同的隐性致病变异的概率为0.03(39/1146),有阳性家族史者为0.08(4/53)。结论对传统遗传学检测为阴性的先天性结构异常胎儿进行全外显子组测序,可额外检出13.9%与表型相关的致病性/可能致病性基因变异,其对于产前诊断的价值因受累器官不同而存在差异。通过随访,对孕晚期或出生后出现新增表型的病例进行测序数据重分析可进一步提高诊断率。可针对特定病种深入研究,进一步探讨相关的遗传学机制。Objective To investigate the application value of whole exome sequencing technology in fetuses with congenital structural abnormalities.Methods The chromosomal abnormalities of 1147 families were analyzed.According to the follow-up results,the data of fetuses with new phenotypes in late pregnancy or after birth were reanalyzed.Subgroups were divided according to the organs involved and whether single malformation or not.The gene regulatory network map was drawn by using string database and Cytoscape software.Fisher exact probability method was used to compare the difference of the diagnostic rate of pathogenic genes among the groups.Results A total of 160 fetal cases received positive molecular diagnosed,involving 178 variant sites of 125 pathogenic genes,including 8 cases(4.9%,8/163)by data reanalysis,and the overall positive diagnosis rate was 13.9%.Diagnostic rate was highest in the group of skeletal malformation(31.5%,39/124)and lowest in that with thoracic malformation(0,0/32).The gene clusters of fetal edema and intrauterine growth restriction were independent,and were not associated with the major structural malformations.The probability of each parent carrying the same recessive gene variant was 0.03(39/1146)and 0.08(4/53)with positive family history.Conclusion For fetuses with congenital structural abnormalities that are negative for conventional genetic tests,13.9%of phenotypic associated pathogenic/likely pathogenic genetic variants can be detected by whole exome sequencing technology.Its application value for prenatal diagnosis varies in fetus with different organs involved.Reanalysis of sequencing data for cases with new phenotypes in late pregnancy or after birth can further improve the molecular diagnosis rate.Further investigations are needed to explore the related genetic mechanisms.

关 键 词：全外显子组测序 结构异常 产前诊断 数据重分析 单基因遗传病 

分 类 号：R440[医药卫生—诊断学] R714.5[医药卫生—临床医学]