Sequencing of a Chinese tetralogy of Fallot cohort reveals clustering mutations in myogenic heart progenitors
Clara Sze Man Tang, Mimmi Mononen, Wai-Yee Lam, Sheng Chih Jin, Xuehan Zhuang, Maria-Mercè Garcia-Barcelo, Qiongfen Lin, Yujia Yang, Makoto Sahara, Elif Eroglu, Kenneth R. Chien, Haifa Hong, Paul Kwong Hang Tam, Peter J. Gruber
Clara Sze Man Tang, Mimmi Mononen, Wai-Yee Lam, Sheng Chih Jin, Xuehan Zhuang, Maria-Mercè Garcia-Barcelo, Qiongfen Lin, Yujia Yang, Makoto Sahara, Elif Eroglu, Kenneth R. Chien, Haifa Hong, Paul Kwong Hang Tam, Peter J. Gruber
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Research Article Cardiology Development

Sequencing of a Chinese tetralogy of Fallot cohort reveals clustering mutations in myogenic heart progenitors

Abstract

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.

Authors

Clara Sze Man Tang, Mimmi Mononen, Wai-Yee Lam, Sheng Chih Jin, Xuehan Zhuang, Maria-Mercè Garcia-Barcelo, Qiongfen Lin, Yujia Yang, Makoto Sahara, Elif Eroglu, Kenneth R. Chien, Haifa Hong, Paul Kwong Hang Tam, Peter J. Gruber

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Figure 5

Gene enrichment of de novo damaging variants in cell type clusters implicated in single-cell and spatial transcriptomics.

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Gene enrichment of de novo damaging variants in cell type clusters impli...
Color of the bars reflects the enrichment among the Chinese only (left; orange) or European only (right; teal) analyses. (A) Human embryonic cardiac cell types identified by single-cell RNA sequencing from Figure 3 in Asp et al. (24); (B) clusters of the anatomical embryonic cardiac regions of spatial transcriptomic data from Figure 2 in Asp et al. (24); (C) cell type clusters identified by single-cell RNA sequencing of in vitro human embryonic stem cell cardiac differentiation in Mononen et al. (25); (D) cell type clusters from human embryonic/fetal heart–derived single-cell RNA sequencing in Sahara et al. (26). Cell types with significant enrichment of DNMs (P < 0.01; dotted lines) are highlighted in bold. Numbers in parentheses indicate the total number of genes analyzed in each category/cluster.