Abstract 16747: High Incidence of Congenital Heart Defects in a Dominant Mouse Forward Genetic Screen Using Fetal Echocardiography

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Introduction: Congenital heart disease (CHD) is largely sporadic and suggested to be largely mediated by non-Mendelian or complex genetics. We previously showed the efficacy of mouse mutagenesis in recovering recessive mutations causing CHD. Here we hypothesize the complex genetics of human CHD can be modeled in mice using a sensitized mutagenesis screen for dominant mutations causing CHD. Methods: C57BL/6J mice were mutagenized using ethylnirosourea, then mated with C57BL/6J mice to generate G1 males that were further mated to females harboring heterozygous “driver” mutation ( Kif7, Anks6, Sap130 ) that can cause CHD when in homozygosity. The G2 fetuses generated by each G1 male were considered a pedigree and were ultrasound scanned (US) at E13.5-19.5 using a 40 MHz transducer with the Vevo2100 ultrasound system. Results: We US scanned 17,750 fetuses from 487 G1 pedigrees, yielding 123 fetuses with CHD from 90 G1 lines (Table 1A). Interestingly, the overall incidence of CHD (0.69%) is similar to that observed in the previous recessive mutagenesis screen (0.76%) (Table 1A). Surprisingly, no laterality mutants were recovered compared to the 2.2% recovered in the recessive screen (Table 1A). Regardless of the driver mutations, similar spectrum of CHD was observed (Table 1B). Besides VSD, the predominant CHD phenotype observed was double outlet right ventricle and overriding aorta (Fig.1) and atrioventricular septal defect (Table 1B). Conclusion: We showed the feasibility of using mice to model dominant mutations causing CHD. The incidence of CHD observed in the dominant screen was similar to that of the recessive screen, indicating the genetics of CHD in mice and human are similar.