Dysregulated fetal heart contraction underlies complex genetics of congenital heart disease

Abstract

Abstract The etiology of most CHD is believed to be multifactorial, potentially involving multiple concurrent genetic mutations. This study employed a large-scale ENU-based forward dominant screen in mice to explore potential novel oligogenic causes of CHD. Through screening 10,000 mice, we identified over 1,000 CHD fetuses, with ventricular septal defects and bicuspid aortic valves being the most prevalent types of defects. Analysis of whole exomes from 720 CHD and 611 control littermates revealed that the CHD group exhibited a significant excess of induced damaging mutations involved in heart contraction and nervous system development. A subsequent gene-based burden test on rare inherited damaging variants from 1457 human CHD probands also revealed enrichment of genes associated with heart contraction and nervous system development. By combining the data from both mice and humans, we proposed a list of oligo gene groups that were found to co-occur in mice and multiple CHD patients but not in control subjects. Our findings shed light on the importance of early hemodynamic perturbations in the developing heart as a previously unrecognized major risk factor for CHD. Further validation and investigation of the identified candidate genes will contribute to a deeper understanding of the molecular mechanisms underlying CHD and may offer insights into novel diagnostic and therapeutic approaches.