胎儿圆锥动脉干畸形的遗传学病因及拷贝数变异测序和全外显子组测序在其中的意义:196例分析  

Genetic etiology of fetal conotruncal defects and significance of copy number variation sequencing and whole exome sequencing:analysis of 196 cases

作　　者：郝晓艳[1] 亦桐 孙海瑞 张烨[1] 谷孝艳[1] 韩建成[1] 何怡华[1] Xiaoyan Hao;Tong Yi;Hairui Sun;Ye Zhang;Xiaoyan Gu;Jiancheng Han;Yihua He(Echocardiography Medical Center,Beijing Anzhen Hospital,Capital Medical University(Maternal-Fetal Medicine Center of Fetal Heart Disease,Beijing Anzhen Hospital),Beijing 100029,China)

机构地区：[1]首都医科大学附属北京安贞医院心脏超声医学中心(北京安贞医院胎儿心脏病母胎医学中心),北京100029

出　　处：《中华围产医学杂志》2023年第4期270-276,共7页Chinese Journal of Perinatal Medicine

基　　金：胎儿心脏病母胎医学研究北京市重点实验室(BZ0308);国家自然科学基金(82200334)。

摘　　要：目的探讨胎儿圆锥动脉干畸形(conotruncal defects,CTDs)的遗传学病因及拷贝数变异测序(copy number variation sequencing,CNV-seq)和全外显子组测序(whole exome sequencing,WES)在其遗传学病因检测中的意义。方法回顾性纳入2017年6月至2021年12月于首都医科大学附属北京安贞医院行超声心动图检查诊断为CTDs的胎儿196例。对其小家系(胎儿及其父母)先行CNV-seq筛查染色体异常[非整倍体及拷贝数变异(copy number variation,CNV)],未检出染色体异常的病例行WES。总结不同分型CTDs的遗传学异常(非整倍体+CNV+单核苷酸变异)以及CNV-seq和WES的检出异常情况,采用χ^(2)检验进行统计学分析。结果CNV-seq检出54例胎儿染色体异常(27.6%,54/196),包括非整倍体14例(7.1%,14/196),CNV 39例(19.9%,39/196),非整倍体合并CNV 1例。CNV-seq未检出异常的142例接受WES,检出13例致病性或可能致病单核苷酸变异。196例CTDs胎儿遗传学异常检出率为34.2%(67/196)。WES使CTDs胎儿的遗传学异常检出率提高了9.2%(13/142)。不同分型CTDs遗传学异常检出率差异有统计学意义(χ^(2)=20.31,P=0.002);主动脉弓离断(B型)、肺动脉瓣缺如综合征(法洛四联症型)的遗传学异常检出率较高,分别为9/10和8/12,大动脉转位的遗传学异常检出率最低(12.5%,5/40)。结论CTDs的遗传学异常以CNV常见,单核苷酸变异在CTDs遗传学异常中也占一定比例。建议CTDs胎儿均进行遗传学检测,条件允许的情况下可以联合应用CNV-seq和WES,有助于提高遗传学病因的检出率,以指导遗传咨询。Objective To investigate the genetic etiology of fetal conotruncal heart defects(CTDs)and to evaluate the performance of copy number variation sequencing(CNV-seq)and whole exome sequencing(WES)in identifying the genetic etiology.Methods This retrospective study involved 196 fetuses diagnosed with CTDs by fetal echocardiography in Beijing Anzhen Hospital,Capital Medical University from June 2017 to December 2021.CNV-seq was performed to screen for chromosomal abnormalities[aneuploidy and copy number variations(CNVs)]in the fetuses and their parents,and then WES was performed if CNV-seq was negative.The diagnostic yields of genetic abnormalities[aneuploidy+CNVs+single nucleotide variations(SNVs)]for different types of CTDs were compared using Chi-square test.Results CNV-seq revealed 54 cases(27.6%,54/196)with chromosomal abnormalities,including 14(7.1%,14/196)aneuploidies,39(19.9%,39/196)CNVs and one aneuploidy complicated by CNVs.Together with another 13 fetuses with pathogenic or likely pathogenic SNVs detected by WES among the rest 142 cases whose CNV-seq results were negative,the total detection rate of genetic abnormalities was 34.2%(67/196).WES increased the diagnostic yield for CTDs by 9.2%(13/142).There was significant difference in the diagnostic yields for different types of CTDs(χ^(2)=20.31,P=0.002).The diagnostic yield was relatively high for interrupted aortic arch of type B,absent of the pulmonary valve-type of tetralogy of Fallot(9/10 and 8/12),but low for transposition of the great arteries(12.5%,5/40).Conclusions CNVs are the common genetic abnormalities in fetal CTDs,and SNVs are also detected in some cases.It is recommended that all fetuses with CTDs should undergo genetic testing.CNV-seq should be used in combination with WES if possible to improve the identification of genetic etiology and provide reference for genetic counseling.

关 键 词：心脏缺损 先天性 DNA拷贝数变异 全外显子组测序 

分 类 号：R714.5[医药卫生—妇产科学]