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.
Highlights
Human cardiovascular disease (CVD) is multifactorial with genetic and exogenous contributors
We identified structural and functional cardiac abnormalities in adult mice by clinical in vivo ECG and transthoracic echocardiography (TTE) and by ex situ iodine contrast high-spatial-resolution microcomputed tomography imaging of embryo hearts to reproduce the effects of known genes and identify hitherto unknown genes that as null alleles corresponded to congenital monogenic cardiac rhythm disorders, cardiomyopathies and structural heart defects
We used in vivo ECG and echocardiography of young adult mice and high-resolution micro-CT imaging of embryos to identify 705 single-gene-knockout mouse lines with cardiac abnormalities
Summary
Human cardiovascular disease (CVD) is multifactorial with genetic and exogenous contributors. Almost all areas of clinical adult and pediatric cardiology include many rare CVDs that are associated with complex underlying genetic etiologies. These genetic disorders include subsets of inherited arrhythmias, cardiomyopathies, vascular diseases and/or structural heart defects that present as heterogeneous phenotypes with variable penetrance and expression[1]. Any changes in ECG intervals can indicate abnormalities in cardiac conduction or electrical instability of the heart muscle leading to cardiac arrhythmia. Clinical manifestations include systolic or diastolic dysfunction Abnormalities on echocardiography, such as enlarged ventricular chambers (that is, dilatation), myocardial wall thickening (that is, hypertrophy) or left ventricular (LV) systolic dysfunction indicate pathologic myocardial remodeling and/ or cardiomyopathies. Isolated VSD4 occurs in approximately two to six of every 1,000 live births and accounts for more than 20% of all human congenital heart disease (CHD), making it the second most common congenital heart defect after bicuspid aortic valve defects[5]
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