Increased adhesiveness of trisomy 21 cells and atrioventricular canal malformations in down syndrome: A stochastic model

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Abstract
Based on the finding that fetal trisomy 21 fibroblasts explanted from lungs and endocardial‐cushion‐derived structures appear more adhesive in vitro than those from normal control individuals, we present a stochastic model for atrioventricular (AV) canal malformations in Down syndrome (DS). Computer simulations were performed to model the normal anatomic sequences of cushion‐to‐cushion and cushion‐to‐septum fusion in AV canal development. In these simulations, randomwalking endocardial cells were allowed to migrate, divide, and adhere with programmable probabilities. Low values of intercellular adhesiveness engendered simulations resembling normal AV canal development; higher values of adhesiveness yielded deficiencies of AV canal development as seen in DS. Moderately high levels of adhesiveness resulted in abnormalities in only a proportion of multiple, independently performed simulations. The model successfully predicts the temporospatial sequence of anatomic events in cushion‐to‐septum fusion, clinical variability among individuals with the same genotype based on chance alone, and amplified developmental instability as observed in individuals with DS.