Gene-environment interactions modulate the phenotypic 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. Defining 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-familial and intra-familial variability. A classic example of this is Treacher Collins Syndrome (TCS), which, although primarily caused by mutations in 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/Treacle protein and reactive oxygen species (ROS) within distinct genetic backgrounds correlates with TCS phenotype severity. Furthermore, geometric morphometric analyses revealed that genotype largely determines the craniofacial shape, but 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 phenotypic severity of craniofacial anomalies.