Publication Date
2-1-2022
Journal
Nature Cardiovascular Research
DOI
10.1038/s44161-022-00018-8
PMID
39195995
PMCID
PMC11358025
PubMedCentral® Posted Date
2-17-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Genetic predisposition to disease, Cardiovascular genetics
Abstract
Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease.
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Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Cardiology Commons, Genetics Commons, Genomics Commons, Medical Sciences Commons
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