Aims

Cardiac malformations are prevalent in trisomies of human chromosome 21 [Down's syndrome (DS)], affecting normal chamber separation in the developing heart. Efforts to understand the aetiology of these defects have been severely hampered by the absence of an accurate mouse model. Such models have proved challenging to establish because synteny with human chromosome Hsa21 is distributed across three mouse chromosomes. None of those engineered so far accurately models the full range of DS cardiac phenotypes, in particular the profound disruptions resulting from atrioventricular septal defects (AVSDs). Here, we present analysis of the cardiac malformations exhibited by embryos of the transchromosomic mouse line Tc(Hsa21)1TybEmcf (Tc1) which contains more than 90% of chromosome Hsa21 in addition to the normal diploid mouse genome.
Methods and results

Using high-resolution episcopic microscopy and three-dimensional (3D) modelling, we show that Tc1 embryos exhibit many of the cardiac defects found in DS, including balanced AVSD with single and separate valvar orifices, membranous and muscular ventricular septal defects along with outflow tract and valve leaflet abnormalities. Frequencies of cardiac malformations (ranging from 38 to 55%) are dependent on strain background. In contrast, no comparable cardiac defects were detected in embryos of the more limited mouse trisomy model, Dp(16Cbr1-ORF9)1Rhr (Ts1Rhr), indicating that trisomy of the region syntenic to the Down's syndrome critical region, including the candidate genes DSCAM and DYRK1A, is insufficient to yield DS cardiac abnormalities.
Conclusion

The Tc1 mouse line provides a suitable model for studying the underlying genetic causes of the DS AVSD cardiac phenotype.