Insights into the genetic landscape of congenital heart disease with a systems genetic approach

A systems genetic approach with mouse forward genetic screen has revealed an unexpected central role for cilia in the pathogenesis of congenital heart disease (CHD). Using noninvasive fetal echocardiography for cardiovascular phenotyping, we screened 100,000 fetal mice in a large scale mutagenesis screen. Over 300 mutant lines with a wide spectrum of CHD were recovered. Whole mouse exome sequencing analysis recovered 147 pathogenic mutations in 100 genes causing CHD. Surprising the majority of genes recovered from this phenotype based screen were cilia related, suggesting a central role for cilia in CHD pathogenesis. Based on the screen metrics, we estimate there are 276 CHD genes in the mouse genome causing CHD, indicating our screen is at ~30% saturation. As many of the CHD genes encoded proteins that are direct protein interacting partners, they suggest a CHD protein interactome may comprise the genomic context underlying the complex genetics of CHD.

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