Decoding Genetics of Congenital Heart Disease Using Patient-Derived Induced Pluripotent Stem Cells (iPSCs).
Decoding Genetics of Congenital Heart Disease Using Patient-Derived Induced Pluripotent Stem Cells (iPSCs).
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DOI：
10.3389/fcell.2021.630069
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhao MT
中科院分区：
文献类型：
--
作者：
Lin H;McBride KL;Garg V;Zhao MT
先天性心脏病（CHD）是与出生缺陷相关的婴儿死亡的最常见原因。最近的下一代基因组测序揭示了CHD的新遗传病因，从遗传和新生变异到非编码遗传变异。了解CHD遗传因素的下一阶段将是在细胞和动物模型系统中对该基因组测序数据进行功能说明和验证。人类诱导多能干细胞（iPSC）为研究CHD的遗传机制开辟了新的视野，其使用临床相关和患者特异性心脏细胞，如心肌细胞、内皮/内皮细胞、心脏成纤维细胞和血管平滑肌细胞。使用尖端的CRISPR/Cas9基因组编辑工具，可以在患病的iPSC中纠正给定的遗传变异，并将其引入健康的iPSC中，以确定变异的致病性和CHD的分子基础。在这篇综述中，我们讨论了通过大规模基因组测序破译的CHD遗传学的最新进展，并探讨了基因组编辑的患者iPSC如何通过与单细胞基因组学和类器官技术相结合来解码CHD的遗传病因。
Congenital heart disease (CHD) is the most common cause of infant death associated with birth defects. Recent next-generation genome sequencing has uncovered novel genetic etiologies of CHD, from inherited and de novo variants to non-coding genetic variants. The next phase of understanding the genetic contributors of CHD will be the functional illustration and validation of this genome sequencing data in cellular and animal model systems. Human induced pluripotent stem cells (iPSCs) have opened up new horizons to investigate genetic mechanisms of CHD using clinically relevant and patient-specific cardiac cells such as cardiomyocytes, endothelial/endocardial cells, cardiac fibroblasts and vascular smooth muscle cells. Using cutting-edge CRISPR/Cas9 genome editing tools, a given genetic variant can be corrected in diseased iPSCs and introduced to healthy iPSCs to define the pathogenicity of the variant and molecular basis of CHD. In this review, we discuss the recent progress in genetics of CHD deciphered by large-scale genome sequencing and explore how genome-edited patient iPSCs are poised to decode the genetic etiologies of CHD by coupling with single-cell genomics and organoid technologies.
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