Craniofacial morphology of <scp>TcMAC21</scp> and <scp>TcHSA21rat</scp> models of Down syndrome: An interspecific comparison

Down syndrome (DS) is caused by an extra copy of human chromosome 21 (HSA21) and is associated with significant craniofacial anomalies among other systemic traits. While animal models have been pivotal in advancing DS research, most of the mouse models replicate only a portion of the human genetic condition. The recently developed transchromosomic rodent models of DS, TcMAC21 mice, and TcHSA21rat carry nearly complete copies of HSA21q and all of HSA21, respectively. While both TcMAC21 and TcHSA21rat express DS-like craniofacial malformations, no comprehensive interspecies comparisons have been conducted between the two. Here, we quantitatively compare the craniofacial skeleton of TcMAC21, TcHSA21rat, and their respective unaffected littermates using high-resolution micro-computed tomography images, landmark-based geometric morphometrics, and advanced multivariate statistics to assess overall craniofacial shape and integration patterns between the neurocranial and facial components. Both models reflect the craniofacial morphology of DS, exhibiting increased neurocranial globularity (supero-inferiorly) and overall facial retraction (anteroposteriorly). However, the rat model expresses a more prominent brachycephalic phenotype compared with its murine counterpart. The integration between the cranial components was found to be evolutionarily conserved across species; however, the trisomic animals maintained their distinct DS-specific configuration compared with their euploid littermates. Our findings establish a methodological framework for cross-species comparisons in DS animal models and provide important insights into characteristic manifestations of trisomy 21 and evolutionarily conserved aspects of the mammalian craniofacial skeleton.