Nuclear Factor One X(NFIX)haploinsufficiency in humans results in Malan syndrome, a disorder characterized by overgrowth, macrocephaly and intellectual disability. Although clinical assessments have determined the underlying symptomology of Malan syndrome, the fundamental mechanisms contributing to their enlarged head circumference and intellectual disability in these patients remains undefined. Here, we usedNfix heterozygous mice as a model to investigate these aspects of Malan syndrome. We reveal, using magnetic resonance imaging, that brain volume is significantly increased within adult Nfix+/-mice, most markedly within the cerebral cortex. Moreover, using diffusion magnetic resonance imaging and tractography-based analyses, we reveal microstructural deficits within major forebrain commissures and aberrant connectivity between many crucial brain regions. Finally, we demonstrate that Nfix+/-mice exhibit cortically-mediated behavioral deficits that model intellectual disability. Collectively, these data provide a significant conceptual advance in our understanding of Malan syndrome by suggesting that megalencephaly underlies the enlarged head size of these patients, and that disrupted cortical connectivity may contribute to the intellectual disability these patients exhibit.