Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier

Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart and thus trisomy 21 is not sufficient by itself to cause CHD. Ts65Dn mice are trisomic for orthologs of more than 100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn significantly increases the penetrance of heart defects. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about 2/3 of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1 -mediated septal defects in Ts65Dn. Thus, over-expression of the trisomic gene, Jam2 , is a necessary potentiator of the disomic genetic modifier, Creld1 . No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified but Jam2 (and its environs) have not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single gene models.