胎儿先天性心脏病产前基因诊断的现状及展望

doi:10.3969/j.issn.1674-8115.2022.10.017

摘要/Abstract

摘要：

先天性心脏病（congenital heart disease，CHD）指因遗传或环境因素引起心脏或血管结构异常，导致心功能出现障碍的出生缺陷，是近年来我国出生缺陷病种中排名第1位的疾病。CHD发病率呈逐年上升趋势，严重影响着新生儿的健康，尤其是某些复杂性CHD患儿，其出生存活率极低且需要外科手术干预，给患儿家庭带来了沉重的心理和经济负担。CHD的病因复杂，目前国内外相关研究都认为CHD的发生与遗传、环境因素密切相关。相关调查研究显示遗传因素是CHD的主要病因之一，大约每10个CHD患儿中就有1个和基因遗传有关，故产前诊断探索胎儿CHD遗传致病病因，对于评估胎儿预后至关重要。近年来，国内外越来越多的研究聚焦于CHD的遗传病因，但综合性总结产前基因诊断检测技术的综述较少，该文就目前CHD遗传病因相关的产前诊断检测技术的研究进展做一综述。

关键词: 先天性心脏病, 产前诊断, 染色体微阵列技术, 全外显子测序

Abstract:

Congenital heart disease (CHD) is diagnosed as the birth defect that causes heart or blood vessel structure abnormality due to genetic or environmental factors, leading to cardiac dysfunction. It is the most common disease among birth defects in China recently, and its incidence is increasing year by year, seriously affecting the health of newborns, especially for some complicated CHD fetuses. The birth survival rate is very low, and surgical interventions are necessary, which bring heavy psychological and economic burden to the families of fetuses, and seriously affect the aristogenesis and aristogenesis in China. The etiology of CHD is complex. Nowadays, it is believed that the occurrence of CHD is closely related to genetic and environmental factors. Some studies showed that genetic factors were the main causes of CHD, and approximately one of ten fetuses with CHD were related to genetic inheritance. Therefore, prenatal diagnosis to investigate the genetic causes of fetal CHD is crucial for evaluating fetal prognosis. In recent years, more and more studies at home and abroad have focused on the genetic etiology of congenital heart disease. Relevant review articles published in China only focused on the progress of certain genetic testing techniques for the detection of chromosomal abnormalities of CHD, and there is still a lack of comprehensive summary of various prenatal genetic testing techniques on the detection of genetic causes of CHD. This article reviews and prospects various genetic testing techniques for CHD.

Key words: congenital heart disease (CHD), prenatal diagnosis, chromosomal microarray analysis, whole exome sequencing

中图分类号:

R715.5

李敏, 吴怡, 程蔚蔚. 胎儿先天性心脏病产前基因诊断的现状及展望[J]. 上海交通大学学报（医学版）, 2022, 42(10): 1498-1503.

LI Min, WU Yi, CHENG Weiwei. Status and prospect of prenatal genetic diagnosis of fetal congenital heart disease[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(10): 1498-1503.

参考文献 40

1	ZAIDI S, BRUECKNER M. Genetics and genomics of congenital heart disease[J]. Circ Res, 2017, 120(6): 923-940.
2	PIERPONT M E,BRUECKNER M,CHUNG W K,et al. Genetic basis for congenital heart disease: revisited: a scientific statement from the american heart association[J]. Circulation, 2018, 138(21): e653-e711.
3	HOPKINS M K, DUGOFF L, KULLER J A. Congenital heart disease: prenatal diagnosis and genetic associations[J]. Obstet Gynecol Surv, 2019, 74(8): 497-503.
4	LIU Y J, CHEN S, ZÜHLKE L, et al. Global birth prevalence of congenital heart defects 1970‒2017: updated systematic review and meta-analysis of 260 studies[J]. Int J Epidemiol, 2019, 48(2): 455-463.
5	BOUMA B J, MULDER B J M. Changing landscape of congenital heart disease[J]. Circ Res, 2017, 120(6): 908-922.
6	TREVISAN P, ROSA R F M, KOSHIYAMA D B, et al. Congenital heart disease and chromossomopathies detected by the karyotype[J]. Rev Paul Pediatr, 2014, 32(2): 262-271.
7	郭辉, 林琳华, 任景慧, 等. 产前超声诊断胎儿先天性心脏病中染色体核型异常的分析[J]. 中国优生与遗传杂志, 2014, 22(7): 38-39.
	GUO H, LIN L H, REN J H, et al. Analysis of abnormal chromosome karyotype in the diagnosis of fetal congenital heart disease by prenatal ultrasound[J]. Chinese Journal of Birth Health & Heredity, 2014, 22(7): 38-39.
8	游艳琴, 李亚里. 荧光原位杂交技术在产科相关领域的应用[J]. 国际妇产科学杂志, 2013, 40(5): 420-423.
	YOU Y Q, LI Y L. Application of fluorescence in situ hybridization technology in obstetric-related fields[J]. J Int Obstet Gynecol, 2013, 40(5): 420-423.
9	GOLDMUNTZ E. 22q11.2 deletion syndrome and congenital heart disease[J]. Am J Med Genet C Semin Med Genet, 2020, 184(1): 64-72.
10	赵婧, 黄湘, 李红艳, 等. 荧光原位杂交技术在先天性心脏病产前诊断中的应用[J]. 检验医学与临床, 2015, 12(23): 3512-3514.
	ZHAO J, HUANG X, LI H Y,et al. Application of fluorescence in situ hybridization in prenatal diagnosis of congenital heart disease[J]. Lab Med Clin, 2015, 12(23): 3512-3514.
11	GEDDES G C, BUTTERLY M, SAJAN I. FISH for 22q11.2 deletion not cost-effective for infants with congenital heart disease with microarray[J]. Pediatr Cardiol, 2015, 36(3): 531-536.
12	辛毅, 潘晓冬, 刘晴, 等. 荧光原位杂交技术产前诊断先天性心脏病22q11.2微缺失应用价值[J]. 心肺血管病杂志, 2012, 31(3): 236-240.
	XIN Y, PAN X D, LIU Q, et al. Application value of fluorescence in situ hybridization in prenatal diagnosis of congenital heart disease with 22q11.2 microdeletion[J]. J Cardiovasc Pulm Dis, 2012, 31(3): 236-240.
13	徐志红, 文强, 王秀, 等. 产前全外显子组测序技术的应用进展[J]. 中国优生与遗传杂志, 2020, 28(3): 390-393.
	XU Z H,WEN Q,WANG X,et al. Application progress of prenatal whole exome sequencing technology[J]. Chinese Journal of Birth Health & Heredity, 2020, 28(3): 390-393.
14	汪敏, 赵绍杰, 卢斌, 等. 染色体微阵列分析技术在先天性心脏病胎儿中的临床应用[J]. 现代妇产科进展,2021, 30(2): 133-136, 140.
	WANG M,ZHAO S J,LU B,et al. Clinical application of chromosomal microarray analysis technology in fetuses with congenital heart disease[J]. Progress in Obstetrics and Gynecology, 2021, 30(2): 133-136, 140.
15	LEVY B, WAPNER R. Prenatal diagnosis by chromosomal microarray analysis[J]. Fertil Steril, 2018, 109(2): 201-212.
16	HALDER A, JAIN M, KALSI A K. SNP microarray in FISH negative clinically suspected 22q11.2 microdeletion syndrome[J]. Scientifica, 2016, 2016: 5826431.
17	WANG Y, CAO L, LIANG D, et al. Prenatal chromosomal microarray analysis in fetuses with congenital heart disease: a prospective cohort study[J]. Am J Obstet Gynecol, 2018, 218(2): 244.e1-244.e17.
18	王桂喜, 孙锟, 孔令晖, 等. SNP array分析技术在胎儿先天性心脏病诊断中的价值[J]. 临床儿科杂志, 2021, 39(10): 726-728.
	WANG G X, SUN K, KONG L H, et al. The value of SNP array analysis technology in the diagnosis offetal congenital heart disease[J]. J Clin Pediatr, 2021, 39(10): 726-728.
19	汪敏, 肖建平, 赵丽, 等. 染色体微阵列分析技术在先天性心脏病胎儿遗传病因学诊断中的临床价值[J]. 中国实用妇科与产科杂志, 2022, 38(3): 359-362.
	WANG M, XIAO J P, ZHAO L, et al. Clinical value of chromosomal microarray analysis technology in the diagnosis of fetal genetic etiology of congenital heart disease[J]. Chin J Pract Gynecol Obstet, 2022, 38(3): 359-362.
20	Society for Maternal-Fetal Medicine (SMFM) Electronic Address: pubs@smfm org, DUGOFF L, NORTON M E, et al. The use of chromosomal microarray for prenatal diagnosis[J]. Am J Obstet Gynecol, 2016, 215(4): B2-B9.
21	ARMOUR C M, DOUGAN S D, BROCK J A, et al. Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada[J]. J Med Genet, 2018, 55(4): 215-221.
22	MILLER D T, ADAM M P, ARADHYA S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies[J]. Am J Hum Genet, 2010, 86(5): 749-764.
23	中华医学会医学遗传学分会临床遗传学组, 中国医师协会医学遗传医师分会遗传病产前诊断专业委员会, 中华预防医学会出生缺陷预防与控制专业委员会遗传病防控学组. 低深度全基因组测序技术在产前诊断中的应用专家共识[J]. 中华医学遗传学杂志, 2019, 36(4): 293-296.
	Clinical Genetics Group, Medical Genetics Branch of Chinese Medical Association, Professional Committee of Prenatal Diagnosis of Genetic Diseases, Medical Geneticists Branch of Chinese Medical Doctor Association, Genetic Disease Prevention and Control Group of Birth Defect Prevention and Control Professional Committee of Chinese Preventive Medicine Association. Expert consensus on the application of low-depth whole genome sequencing technology in prenatal diagnosis[J]. Chin J Med Genet, 2019(4): 293-296.
24	李奉瑾, 姚欣雨, 张玉萍. 低深度全基因组测序技术在产前诊断中的研究进展[J]. 国际妇产科学杂志, 2021, 48(1):75-78, 83.
	LI F J,YAO X Y,ZHANG Y P. Research progress of low-depth whole genome sequencing technology in prenatal diagnosis[J]. J Int Obstet Gynecol, 2021, 48(1): 75-78, 83
25	ZHU XY, LI J, RU T, et al. Identification of copy number variations associated with congenital heart disease by chromosomal microarray analysis and next-generation sequencing[J]. Prenat Diagn, 2016, 36(4): 321-327.
26	邓新娥, 黄杏玲, 王远流, 等. 拷贝数变异测序在胎儿先天性心脏病产前遗传学诊断中的应用[J]. 中国生育健康杂志, 2020, 31(2): 137-142.
	DENG X E,HUANG X L,WANG Y L,et al. Application of copy number variation sequencing in prenatal genetic diagnosis of fetal congenital heart disease[J]. Chinese Journal of Reproductive Health,2020, 31(2): 137-142.
27	LAN L B, SHE L N, ZHANG B S, et al. Prenatal diagnosis of 913 fetuses samples using copy number variation sequencing[J]. J Gene Med, 2021, 23(5): e3324. .
28	LI R, FU F, YU Q X, et al. Prenatal exome sequencing in fetuses with congenital heart defects[J]. Clin Genet, 2020, 98(3): 215-230.
29	QIAO F, WANG Y, ZHANG C, et al. Comprehensive evaluation of genetic variants using chromosomal microarray analysis and exome sequencing in fetuses with congenital heart defect[J]. Ultrasound Obstet Gynecol, 2021, 58(3): 377-387.
30	LORD J, MCMULLAN D J, EBERHARDT R Y, et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study[J]. Lancet, 2019, 393(10173): 747-757.
31	PETROVSKI S, AGGARWAL V, GIORDANO J L, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study[J]. Lancet, 2019, 393(10173): 758-767.
32	FU F, LI L S, DU K, et al. Analysis of families with fetal congenital abnormalities but negative prenatal diagnosis by whole exome sequencing[J]. Zhonghua Fu Chan Ke Za Zhi, 2021, 56(7): 458-466.
33	MONAGHAN K G, LEACH N T, PEKAREK D, et al. The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)[J]. Genet Med, 2020, 22(4): 675-680.
34	DUEÑAS A, EXPÓSITO A, ARANEGA A, et al. The role of non-coding RNA in congenital heart diseases[J]. J Cardiovasc Dev Dis, 2019, 6(2): 15.
35	YANG H N, YANG S P, SHEN H L, et al. Construction of the amniotic fluid-derived exosomal CeRNA network associated with ventricular septal defect[J]. Genomics, 2021, 113(6): 4293-4302.
36	DUEÑAS A, EXPÓSITO A, ARANEGA A, et al. The role of non-coding RNA in congenital heart diseases[J]. J Cardiovasc Dev Dis, 2019, 6(2): 15.
37	WANG Z, QIAO X H, XU Y J, et al. SMAD1 loss-of-function variant responsible for congenital heart disease[J]. Biomed Res Int, 2022, 2022: 9916325.
38	顾卉, 陈骊珠, 薛佳, 等. 先天性心脏病胎儿母体血清中的microRNA表达谱及其诊断意义[J]. 发育医学电子杂志, 2019, 7(1): 32-37.
	GU H,CHEN L Z,XUE J,et al. MicroRNA expression profile in maternal serum of fetuses with congenital heart disease and its diagnostic significance[J]. Journal Developmental Medicine (Electronic Version), 2019, 7(1): 32-37.
39	杨伟, 王峥. 超声心动检查联合孕妇血清miRNA-19b、AFP测定对胎儿先天性心脏病的诊断价值分析[J]. 中国优生与遗传杂志, 2020, 28(5): 618-621.
	YANG W,WANG Z. Analysis of the diagnostic value of echocardiography combined with maternal serum miRNA-19b and AFP determination in fetal congenital heart disease[J]. Chinese Journal of Birth Health & Heredity, 2020, 28(5): 618-21.
40	金玉霞, 李素萍, 艾玲, 等. 孕妇血清中miRNAs作为生物标志物用于胎儿先心病法洛四联症的产前检测[J]. 中国卫生检验杂志, 2021, 31(16): 1931-1934, 1939.
	JIN Y X, LI S P, AI L,et al. Prenatal detection of fetal congenital heart disease tetralogy of Fallot with miRNAs in maternal serum as biomarkers[J]. Chinese Journal of Health Laboratory Technology, 2021, 31(16): 1931-1934, 1939.

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