Deletion size and background genetic variation shape congenital heart disease phenotypes in 3,016 individuals with 22q11.2 deletion syndrome

Congenital heart disease (CHD) occurs in over half of individuals with 22q11.2 deletion syndrome (22q11.2DS) and the types of lesions range from mild to severe. To determine the basis of variation in cardiac phenotypes we analyzed demographic data from 3,016 unrelated individuals with 22q11.2DS from centers in the Northeast US, Canada, Europe, South America, Israel and Australia. Most individuals in this cohort had a 3 million base pair hemizygous deletion between low copy repeat, LCR22 A-D (87.2%), while some had nested deletions. We performed multivariable mixed-effects logistic regression and uncovered significant differences between CHD phenotypes and basic demographic features. Individuals with the A-D deletion had a lower risk of persistent truncus arteriosus (OR = 0.37, 95% CI 0.18-0.75) but a higher risk of septal defects (OR = 4.7, 95% CI 1.7-12.8) compared to those with the smaller A-B deletion, suggesting distinct developmental pathways sensitive to 22q11.2 gene dosage. In addition, genome-wide genetic principal components (PCs) were associated with specific CHD subtypes, including reduced risk of pulmonary stenosis or atresia with other heart lesions (PC2; OR = 0.73, 95% CI 0.61-0.87) and increased risk of abnormal origin of the subclavian arteries (PC4; OR = 2.6, 95% CI 1.4-4.9), indicating that background genetic variation modifies heart lesion-specific susceptibility. Together, these results suggest that both deletion size and background genetic variation shape the highly variable cardiac phenotypes in 22q11.2DS.