Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/deI22q11 syndromes

The del22q11 syndrome is associated with a highly variable phenotype despit e the uniformity of the chromosomal deletion that causes the disease in mos t patients. Df1/+ mice, which model del22q11, present with reduced penetran ce of cardiovascular defects similar to those seen in deleted patients but not with other del22q11-like findings. The reduced penetrance of cardiovasc ular defects is caused by the ability of mutant embryos to recover from a f ourth pharyngeal arch artery growth abnormality that is fully penetrant in early embryos. Here we show that genetic background has a major effect on p enetrance of cardiovascular defects by affecting this embryonic recovery pr ocess. This effect could not be explained by allelic variation at the haplo id locus, and it is likely to be caused by genetic modifiers elsewhere in t he genome. We also show that genetic factors control extension of the Df1/ phenotype to include thymic and parathyroid anomalies, establishing the DO mouse as a model for the genetic analysis of three major features of human del22q11 syndrome. We found that in Df1/+ mice, as in human patients, expr ession of the heart and thymic phenotypes are essentially independent from each other, suggesting that they may be controlled by different genetic mod ifiers. These data provide a framework for our understanding of phenotypic variability in patients with del22q11 syndrome and the tools for its geneti c dissection.