Gene-environment interactions modulate the phenotype severity in mouse models of congenital craniofacial syndromes

Birth defects are the leading cause of infant mortality, and most inborn errors of development are multifactorial in origin resulting from complex gene-environment interactions. Definition of specific gene-environment interactions in the etiology and pathogenesis of congenital disorders is critically needed in the absence of genotype-phenotype correlation but is challenging. This is particularly true for congenital craniofacial anomalies, which account for approximately one-third of all birth defects, as they typically exhibit considerable inter- and intrafamilial variability. A classic example of this is Treacher Collins syndrome (TCS), which, although primarily caused by mutations in treacle ribosome biogenesis factor 1 (TCOF1), is characterized by considerable variability in the severity of mandibulofacial dysostosis. Here, we describe the genetic and environmental factors with converging effects that mechanistically contribute to the etiology and pathogenesis of craniofacial variation in this rare congenital disorder. We discovered in Tcof1+/- mouse models of TCS that the combination of different endogenous levels of Tcof1 (also known as treacle) protein and ROS within distinct genetic backgrounds correlated with TCS phenotype severity. Furthermore, geometric morphometric analyses revealed that genotype largely determines the craniofacial shape but that redox status determines the size of individual bones. Taken together, our results highlight the roles of ROS and genomic instability in modulating the variability and phenotype severity of craniofacial anomalies.