Abstract

Rare copy number variants and sequence variants (single nucleotide variants and short insertions/deletions [indels]) have been shown to increase the risk of congenital heart disease (CHD). Whether these variants contribute to clinical outcomes remains unknown.1 Genes implicated as causing CHD may lead to pathological remodeling through activation of fetal genes in response to physiologic stress. We sought to determine the association of predicted damaging genetic variation with ventricular dysfunction in a CHD cohort who underwent exome sequencing (ES) at Columbia University Medical Center (CUMC).

In our CHD cohort, predicted damaging variants were associated with worsening ventricular function, particularly in those with a single ventricle, and damaging de novo variants in genes that were both constrained and in the top quartile of heart expression had the strongest association with worsening ventricular function. While our study is limited by its reliance on retrospective data, qualitative assessment of ventricular function and proportion of single ventricle patients, these results suggests that damaging variants may impact myocardial function in select individuals with CHD.