Sequencing of a Chinese tetralogy of Fallot cohort reveals clustering mutations in myogenic heart progenitors.
Sequencing of a Chinese tetralogy of Fallot cohort reveals clustering mutations in myogenic heart progenitors.
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DOI：
10.1172/jci.insight.152198
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发表时间：
2022-01-25
期刊：
影响因子：
8
通讯作者：
Gruber PJ
中科院分区：
文献类型：
--
作者：
Tang CSM;Mononen M;Lam WY;Jin SC;Zhuang X;Garcia-Barcelo MM;Lin Q;Yang Y;Sahara M;Eroglu E;Chien KR;Hong H;Tam PKH;Gruber PJ
法洛四联症（TOF）是最常见的紫绀型心脏缺陷，但其潜在的遗传机制仍然知之甚少。在这里，我们进行了全基因组测序分析146非综合征TOF亲子三人组的中国种族。比较从头变异和隐性基因型的数据集与欧洲队列的数据，确定重叠和潜在的新基因位点，并揭示不同的功能富集队列之间。为了评估这些突变对早期心脏发育的影响，我们将早期人类心脏发育的单细胞和空间转录组学与我们的遗传发现相结合。我们发现，候选基因表达富集在心脏流出道的肌源性祖细胞。此外，候选基因的子集被发现在特定的基因共表达模块沿着心肌细胞分化的轨迹。这些综合功能分析有助于剖析TOF的发病机制，揭示导致心脏畸形的早期心脏发育中的细胞热点。
Tetralogy of Fallot (TOF) is the most common cyanotic heart defect, yet the underlying genetic mechanisms remain poorly understood. Here, we performed whole-genome sequencing analysis on 146 nonsyndromic TOF parent-offspring trios of Chinese ethnicity. Comparison of de novo variants and recessive genotypes of this data set with data from a European cohort identified both overlapping and potentially novel gene loci and revealed differential functional enrichment between cohorts. To assess the impact of these mutations on early cardiac development, we integrated single-cell and spatial transcriptomics of early human heart development with our genetic findings. We discovered that the candidate gene expression was enriched in the myogenic progenitors of the cardiac outflow tract. Moreover, subsets of the candidate genes were found in specific gene coexpression modules along the cardiomyocyte differentiation trajectory. These integrative functional analyses help dissect the pathogenesis of TOF, revealing cellular hotspots in early heart development resulting in cardiac malformations.