Resting-State Functional Connectivity and Psychopathology in Klinefelter Syndrome (47, XXY)

Abstract Klinefelter syndrome (47, XXY; henceforth: XXY syndrome) is a high-impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first study to map alterations of functional brain connectivity in XXY syndrome and relate these changes to brain anatomy and psychopathology. We used resting-state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males to 1) implement a brain-wide screen for altered global resting-state functional connectivity (rsFC) in XXY versus XY males and 2) decompose these alterations through seed-based analysis. We then compared these rsFC findings with measures of regional brain anatomy, psychopathology, and cognition. XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC)—reflecting DLPFC overconnectivity with diverse rsFC networks. Functional overconnectivity was partly coupled to co-occurring regional volumetric changes in XXY syndrome, and variation in DLPFC–precuneus rsFC was correlated with the severity of psychopathology. By providing the first view of altered rsFC in XXY syndrome and contextualizing observed changes relative to neuroanatomy and behavior, our study helps to advance biological understanding of XXY syndrome—both as a disorder in its own right and more broadly as a model of genetic risk for psychopathology.