The behavioral neurogenetics of fragile X syndrome: Analyzing gene–brain–behavior relationships in child developmental psychopathologies

Analyzing gene–brain–behavior linkages in childhood neurodevelopmental disorders, a research approach called “behavioral neurogenetics,” has provided new insights into understanding how both genetic and environmental factors contribute to complex variations in typical and atypical human development. Research into etiologically more homogeneous disorders, such as fragile X syndrome, in particular, allows the use of more precise metrics of genetic risk so that we can more fully understand the complex pathophysiology of childhood onset neurodevelopmental disorders. In this paper, we review our laboratory's behavioral neurogenetics research by examining gene–brain–behavior relationships in fragile X syndrome, a single-gene disorder that has become a well-characterized model for studying neurodevelopmental dysfunction in childhood. Specifically, we examine genetic influences, trajectories of cognition and behavior, variation in brain structure and function, and biological and environmental factors that influence developmental and cognitive outcomes of children with fragile X. The converging approaches across these multilevel scientific domains indicate that fragile X, which arises from disruption of a single gene leading to the loss of a specific protein, is associated with a cascade of aberrations in neurodevelopment, resulting in a central nervous system that is suboptimal with respect to structure and function. In turn, structural and functional brain alterations lead to early disruption in emotion, cognition, and behavior in the child with fragile X. The combination of molecular genetics, neuroimaging, and behavioral research have advanced our understanding of the linkages between genetic variables, neurobiological measures, IQ, and behavior. Our research and that of others demonstrates that neurobehavior and neurocognition, genetics, and neuroanatomy are all different views of the same intriguing biological puzzle, a puzzle that today is rapidly emerging into a more complete picture of the intricate linkages among gene, brain, and behavior in developing children. Understanding the complex multilevel scientific perspective involved in fragile X will also contribute to our understanding of normal development by highlighting developmental events throughout the life span, thereby helping us to delineate the boundaries of pathology.