Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births1; the incidence of CHD is up to tenfold higher in human fetuses2,3. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk4. Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and cilia-transduced cell signalling have important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note that the pathways identified show overlap with CHD candidate genes recovered in CHD patients5, suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling.
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We thank R. Ramirez for early assistance with the mutagenesis breeding pipeline, R. Subramanian and D. Farkas for early assistance with necropsy and pathology examination of mutants, A. Srinivasan for early assistance with exome sequencing, S. Fatakia for assistance with sequencing data maintenance, M. Wong and C. Krise for assistance with mouse curation, B. Beutler for advice on mapping mutations using intercrosses with the C57BL/10J strain and whole-mouse exome sequencing analysis, D. Weeks and Y. Shan for assistance in statistical modelling of target gene size estimates, E. Goldmuntz for helpful discussions and critical review of the manuscript, and the New England Research Institutes (NERI) for constructing the CHD Mouse Mutation Database. The project was supported by award numbers U01HL098180 (to C.W.L.) and U01HL098188 (to NERI) from the National Heart, Lung, and Blood Institute, R01MH094564 (to M.K.G.) from the National Institute of Mental Health, and HG000330 (to J.E.) from the National Human Genome Research Institute. Funding was also provided by the University of Pittsburgh School of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, the National Human Genome Research Institute or the National Institutes of Health.
Extended data figures
Vevo 2100 color flow Doppler imaging in coronal view show normal alignment of the two great arteries with normal connection to the two ventricles.
Vevo2100 color flow imaging in coronal view of fetus in Figure 1e-k showed aorta and pulmonary artery side-by side, both emerging from the right ventricle (RV) indicating DORV, and a shunting of blood between the two ventricles indicating ventricular septal defect (VSD).
Vevo 2100 color flow imaging in transverse view of fetus in Figure 1e-k detected forward blood flow and regurgitation from a common atrioventricular valve suggesting atrioventricular septal defect. Also observed was a muscular ventricular septal defect.
Vevo2100 2D imaging in coronal view of fetus in Figure 1e-k detected heart apex pointing to left suggesting levocardia, but stomach (Stom) located on right, which together indicated this fetus has heterotaxy.
Tracheal airway epithelium in a newborn homozygous Foxj1b2b774 mutant mouse shows normal ciliary motion.
Cilia in the embryonic node of a homozygous Foxj1b2b774 mutant embryo shows dyskinetic ciliary motion and no nodal flow.
About this article
Current Opinion in Genetics & Development (2019)