Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a rare genetic disorder associated with serious medical challenges. Most affected individuals have congenital heart disease but with variable phenotypic expression. One of the main questions that is still an open topic in the field is why individuals with 22q11.2DS show extensive phenotypic heterogeneity. Analysis of retrospective data on 3016 individuals with 22q11.2DS and 1868 with sequence data suggests that deletion type and genetic variation influence phenotypic expression of congenital heart disease. This work informs the clinician as to the importance of testing for deletion type and obtaining accurate cardiac phenotypes to diagnose 22q11.2DS that will improve the prognosis and disease progression. It also implicates the complexity of sex and ancestry as confounding factors that will help guide future research studies to identify genetic modifiers…