Key result
Knockout mouse models of human monogenic cardiovascular disease genes frequently exhibited non-viable phenotypes (75.4%) and multisystem abnormalities mimicking clinical manifestations.
Why the study?
Mouse models are relevant for studying gene functionality in human disease, but phenotype translation remains challenging.
Observational (n=153)
Knockout mouse models of human monogenic heart disease frequently exhibit non-viable and multisystem phenotypes, highlighting their utility in understanding pleiotropic gene effects.
Mouse models' high lethality cautions against over-reliance for monogenic CV disease studies; leaves open refined conditional or humanized approaches.
Mouse models are relevant to studying the functionality of genes involved in human diseases; however, translation of phenotypes can be challenging. Here, we investigated genes related to monogenic forms of cardiovascular disease based on the Genomics England PanelApp and aligned them to International Mouse Phenotyping Consortium (IMPC) data. We found 153 genes associated with cardiomyopathy, cardiac arrhythmias or congenital heart disease in humans, of which 151 have one-to-one mouse orthologues. For 37.7% (57/151), viability and heart data captured by electrocardiography, transthoracic echocardiography, morphology and pathology from embryos and young adult mice are available. In knockout mice, 75.4% (43/57) of these genes showed non-viable phenotypes, whereas records of prenatal, neonatal or infant death in humans were found for 35.1% (20/57). Multisystem phenotypes are common, with 58.8% (20/34) of heterozygous (homozygous lethal) and 78.6% (11/14) of homozygous (viable) mice showing cardiovascular, metabolic/homeostasis, musculoskeletal, hematopoietic, nervous system and/or growth abnormalities mimicking the clinical manifestations observed in patients. These IMPC data are critical beyond cardiac diagnostics given their multisystemic nature, allowing detection of abnormalities across physiological systems and providing a valuable resource to understand pleiotropic effects.
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Cacheiro et al. (2023) conducted an observational in Monogenic cardiovascular disease (n=153). Gene knockout was evaluated on Non-viable phenotypes. Knockout mouse models of human monogenic cardiovascular disease genes frequently exhibited non-viable phenotypes (75.4%) and multisystem abnormalities mimicking clinical manifestations.
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