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中华临床医师杂志(电子版) ›› 2023, Vol. 17 ›› Issue (10) : 1090 -1096. doi: 10.3877/cma.j.issn.1674-0785.2023.10.011

综述

全外显子测序技术在先天性心脏病中的应用
云书荣, 王雅晳, 段莎莎, 施依璐, 张敏洁, 张小杉()   
  1. 010050 呼和浩特,内蒙古医科大学附属医院超声科
  • 收稿日期:2023-09-09 出版日期:2023-10-15
  • 通信作者: 张小杉
  • 基金资助:
    国家自然科学基金项目(82360349); 内蒙古自治区科技计划项目(2022YFSH0084)

Application of whole-exon sequencing in congenital heart disease

Shurong Yun, Yaxi Wang, Shasha Duan, Yilu Shi, Minjie Zhang, Xiaoshan Zhang()   

  1. Department of Ultrasound, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
  • Received:2023-09-09 Published:2023-10-15
  • Corresponding author: Xiaoshan Zhang
引用本文:

云书荣, 王雅晳, 段莎莎, 施依璐, 张敏洁, 张小杉. 全外显子测序技术在先天性心脏病中的应用[J]. 中华临床医师杂志(电子版), 2023, 17(10): 1090-1096.

Shurong Yun, Yaxi Wang, Shasha Duan, Yilu Shi, Minjie Zhang, Xiaoshan Zhang. Application of whole-exon sequencing in congenital heart disease[J]. Chinese Journal of Clinicians(Electronic Edition), 2023, 17(10): 1090-1096.

先天性心脏病(CHD)是致死率较高的常见出生缺陷,其发病机制是遗传性与非遗传性因素共同作用的结果。基因突变等遗传性因素通过改变细胞的增殖、凋亡等途径,导致心脏发育障碍。对潜在遗传因素进行分子诊断是该领域的研究热点。全外显子测序(WES)能够识别遗传性疾病的可能致病基因,有助于阐明CHD发展的遗传机制。因其序列覆盖率高,测序周期短、成本低,应用广泛。本文对WES在非综合征型和综合征型 CHD 中的应用进行综述,探讨其在先天性心脏发育缺陷遗传学研究中的应用价值。

Congenital heart disease (CHD) is a common birth defect with high lethality, and its pathogenesis involves both genetic and non-genetic factors. Genetic factors such as gene mutations lead to heart development disorders by changing cell proliferation, apoptosis, and other processes. Molecular diagnosis of the underlying genetic factors is a research hotspot in this field. Whole-exome sequencing can identify possible pathogenic genes of genetic diseases, and help to elucidate the genetic mechanism of CHD development. Because of its high sequence coverage, short sequencing cycle, and low cost, whole-exome sequencing has been widely used in detecting genetic disorders. This paper reviews the use of whole-exome sequencing in non-syndromic and syndromic CHD to investigate its utility in exploring the genetics of congenital cardiac developmental defects.

图1 先天性心脏病的遗传因素。染色体异常、CNVs及单基因突变占所有遗传因素的40%,60%的病因仍然未知
表1 全外显子测序筛查非综合征型先天性心脏病相关易感基因
疾病类型 基因 细胞实验 动物实验 分子机制 样本数 作者 发表时间 发表杂志
TOF TBX1、CD96、BRCA1、RNF135、G6PD、ABCC6、NF1、KCNQ4、APOB、PNPLA2、KLF13、TBX15、ROM1、FLG、GATA4、FOXC2 × × × 19例 Pan Y等 2022 J Thorac Dis.
LRP1 × × 含有1个TOF的家系 Alrayes N等 2022 Gene
MYOM2 × × × 2例 Wang等 2022 Front Cardiovasc Med
OTUD6B × × × 1例 Esra Börklü等 2022 Mol Syndromol
WDR62 237例 Hao等 2022 Clin Transl Med 
SMARCC2 × × × 1例 SUN等 2022 BMC Med Genomics
KDR × 含有2个TOF的家系 Doris Škorić-Milosavljević等 2021 Genet Med
FLNA × × × 含有2个TOF家系 Kalayinia S等 2021 Lab Med
NOTCH1、FLT4、RYR1、ZFPM1、ZNF717、CAMTA 2、DLX 6、PCM 1、TBX 1 × × 829例 Page D J等 2019 Circ Res
AVSD SOX 7 × 13例 Hong等 2021 Cell Death Dis
CCDC14、EVC、PQBP1、ZFPM2、ARMC4、DNAH11 × × × 47例 谷孝艳等 2020 中国医学影像学技术
NR2F2 × × × 1例 Upadia J等 2018 Am J Med Genet A
ASD MYH6 × × 含有3个ASD的家系 Huang S等 2021 Eur J Med Genet
GATA4 × × × 含有3个ASD的家系 Bu等 2021 BMC Cardiovasc Disord
MYH6 × × × 3例 Razmara E等 2018 BMC Cardiovasc Disord
FOXL 2、MYH 6、HYDIN × × × 5例 Liu Y等 2018 Med Sci Monit
LBX 2 × 3例 Wang J等 2018 Int J Cardiol
PCDHGA4、SLFN14 × × × 6例 Su等 2018 Curr Med Sci
VSD NOTCH2、ATIC、MRI1、SLC6A13、ATP13A2 × × × 20例 Zhang等 2023 Pharmgenomics Pers Med
GATA4、MYH 6 × × × 16例 Chaithra S等 2022 Gene
PKP2 × × × 1例 Katanyuwong, P等 2022 Front Pediatr
DNAAF1、TUBA1A、FGFR3、MLL2 × × × 77例 涂鹏等 2020 临床超声医学杂志
PDA PRRX 1 × × 18例 Ke Z P等 2022 Genet Mol Biol
SOX8、NES、CDH2、ANK3、EIF4G1、HIPK1 × × × 39例 Gao Y等 2022 Front Genet
MAP3K1、MYC、VAV2、APLNR、TJP1、CHRNA4 × × × 39例 Chen B等 2020 Front Genet
× × × 1例 Zhou Y等 2018 Int Ophthalmol
表2 全外显子测序筛查综合征型先天性心脏病相关易感基因
HOS GPC3、STAG2、ZFPM2 × × × 1例 张青青等 2023 实用临床医学
TBX5 × × × 含有1个HOS的家系 Azab B等 2022 Mol Med Rep
× × 含有3个HOS的家系 Wang D G等 2022 Am J Med Genet A
× × × 含有1个HOS的家系 Li X等 2022 Heliyon
× × × 含有1个HOS的家系 He G N等 2021 Front Pediatr
SALL4 × × × 1例 Li B等 2018 DNA Cell Biol
NS PTPN11 × × × 8例 Wu X等 2023 Mol Genet Genomic Med
× × × 1例 Hu L等 2021 Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi
× × × 1例 Wang N等 2020 BMC Gastroenterol
× × × 1例 Schönfeld M等 2020 Mol Genet Genomic Med
LZTR1 × × × 1例 Farncombe KM等 2022 BMC Med Genomics
× × × 1例 Kraoua L等 2022 Mol Genet Genomic Med
× × × 含有6个NS的家系 Zhao X等 2021 BMC Endocr Disord
× × × 3例 Güemes M等 2019 Horm Res Paediatr
RIT1 × × × 1例 Qiu Z等 2022 Taiwan J Obstet Gynecol
RRAS2 × × × 1例 Yu C等 2022 Eur J Med Genet
RAF1、RIT1、SOS1、PTPN11、BRAF、SOS2、LZTR1 × × × 22例 Sun L等 2022 Front Genet
NF1 × × × 1例 Zhang等 2020 BMC Pediatr
RAF1 × × × 1例 Jaouadi H等 2019 Genet Res 
RRAS2 3例 Niihori T等 2019 Am J Hum Genet
RAF1 × × × 1例 Jaouadi, H等 2019 Genet Res
EvCS EVC × × 含有1个EvCS的家系 Wang J等 2023 Mol Genet Genomic Med.
× × × 3例 Zaka A等 2021 Am J Med Genet A
× × × 1例 Huang X等 2019 Mol Genet Genomic Med
EVC、EVC2、DYNC2H1、DYNC2LI1、SMO、PRKACB × × × 50例 Aubert-Mucca M等 2023 J Med Genet
EVC2 × × × 1例 Zhuang J等 2023 Mol Genet Genomic Med
× × × 2例 Negrete-Torres N等 2023 Genes (Basel)
× × × 1例 Kantaputra P等 2022 Genes (Basel)
× × × 1例 Eftekhariyazdi M等 2020 J Gene Med
OFCD BCOR × × × 1例 卢园园等 2023 中国当代儿科杂志
× × × 1例 杨滢等 2021 中华围产医学杂志
× × × 16例 Nicola Ragge等 2019 Hum Genet
× × × 1例 Zhou Y等 2018 Int Ophthalmol
表3 OFCD 综合征相关的国内外基因测序文献
表4 先天性心脏病相关的常见综合征
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