TY - JOUR T1 - Systems Analysis of de novo Mutations in Congenital Heart Diseases Identified a Molecular Network in Hypoplastic Left Heart Syndrome JF - bioRxiv DO - 10.1101/2022.06.23.496464 SP - 2022.06.23.496464 AU - Yuejun Jessie Wang AU - Xicheng Zhang AU - Chi Keung Lam AU - Hongchao Guo AU - Cheng Wang AU - Sai Zhang AU - Joseph C. Wu AU - Michael Snyder AU - Jingjing Li Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/06/26/2022.06.23.496464.abstract N2 - Congenital heart diseases (CHD) are a class of birth defects affecting ∼1% of live births. These conditions are hallmarked by extreme genetic heterogeneity, and therefore, despite a strong genetic component, only a very handful of at-risk loci in CHD have been identified. We herein introduced systems analyses to uncover the hidden organization on biological networks of genomic mutations in CHD, and leveraged network analysis techniques to integrate the human interactome, large-scale patient exomes, the fetal heart spatial transcriptomes, and single-cell transcriptomes of clinical samples. We identified a highly connected network in CHD where most of the member proteins had previously uncharacterized functions in regulating fetal heart development. While genes on the network displayed strong enrichment for heart-specific functions, a sub-group, active specifically at early developmental stages, also regulates fetal brain development, thereby providing mechanistic insights into the clinical comorbidities between CHD and neurodevelopmental conditions. At a small scale, we experimentally verified previously uncharacterized cardiac functions of several novel proteins employing cellular assays and gene editing techniques. At a global scale, our study revealed developmental dynamics of the identified CHD network and observed the strongest enrichment for pathogenic mutations in the network specific to hypoplastic left heart syndrome (HLHS). Our single-cell transcriptome analysis further identified pervasive dysregulation of the network in cardiac endothelial cells and the conduction system in the HLHS left ventricle. Taken together, our systems analyses identified novel factors in CHD, revealed key molecular mechanisms in HLHS, and provides a generalizable framework readily applicable to studying many other complex diseases.Competing Interest StatementThe authors have declared no competing interest. ER -