Deletion size and background genetic variation shape congenital heart disease phenotypes in 3016 individuals with 22q11.2 deletion syndrome

Introduction Congenital heart disease (CHD) occurs in over half of individuals with 22q11.2 deletion syndrome (22q11.2DS), but lesion type varies widely. Methods We analysed basic medical features in 3016 unrelated postnatal individuals with 22q11.2DS from specialised centres in the USA, Canada, Europe, South America, Israel and Australia including 1868 with whole-genome sequencing. Results The typical 3 Mb LCR22 A–D deletion was present in 2788 individuals (92.4%), with smaller A–B (n=172, 5.7%) and A–C (n=56, 1.9%) deletions comprising the remaining cohort. In multivariable mixed-effects logistic regression adjusting for sex, deletion group, genome-wide principal components (PCs) and recruitment site, four non-intercept associations to test relationships met study-wide false discovery rate significance. Compared with the A–B deletion, the A–D deletion was associated with lower odds of persistent truncus arteriosus (OR 0.37, 95% CI 0.18 to 0.75) and higher odds of isolated septal defects (OR 4.68, 95% CI 1.71 to 12.83), although precision was limited by the smaller A–B group. PC2 was associated with lower odds of pulmonary stenosis/atresia with additional lesions (OR 0.73, 95% CI 0.61 to 0.87) and PC4 with higher odds of abnormal origin of the subclavian arteries (ASA; OR 2.59, 95% CI 1.37 to 4.89). The Polygenic Risk Score for proximal pulmonary artery diameter was associated with a lower likelihood of ASA (OR 0.71, 95% CI 0.56 to 0.89, p=3.7E−3). ADMIXTURE-derived continental ancestry proportions did not show independent associations with these two PC-associated outcomes. Conclusion These lesion-specific findings in the data presented indicate that the deletion interval on 22q11.2 and broader genetic background may contribute to CHD variability in 22q11.2DS.