Gene burden analysis of 1922 CHD individuals versus 2602 controls with whole-exome sequencing showed a significant excess of rare damaging LRP1 mutations in CHD (odds ratio (OR) = 2.22, p = 1.92 × 10−4), especially in conotruncal defect with OR of 2.37 (p = 1.77 × 10−3) and atrioventricular septal defect with OR of 3.14 (p = 0.0194). This evidence concerns the gene LRP1 and familial atrioventricular septal defect.