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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish
Article numbere152198
JournalJCI Insight
Issue number2
StatePublished - Jan 25 2022


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