It has been estimated that about 10% of patients with autism also carry an identifiable genetic abnormality. One genetic syndrome that confers an increased ASD risk is 22q11.2 deletion syndrome (22q11.2 DS; velocardiofacal syndrome, VCFS), with up to about 40% of the patients developing ASD. The social cognition deficits in 22q11.2 DS patients have not been fully characterized yet, and the additional genetic risk factors and white matter pathology associated with ASD in 22q11.2 DS are unknown. Our study will evaluate Theory of Mind (ToM) (the ability of a person to infer what another person thinks in certain situations) in 22q11.2 DS patients with ASD vs. without ASD and their unaffected siblings. Second, we will use a non-invasive neuroimaging technique (diffusion tensor imaging, DTI) to evaluate the integrity of the white matter tracts of the brain. We predict that 22q11.2 DS patients with ASD will have ToM impairments and white matter abnormalities, compared to the other two groups. Third, we will study the additional genetic risk factors associated with the diagnosis of ASD in 22q11.2 DS, specifically in the genes COMT (which affects neurotransmitter levels in the brain), and PRODH (which degrades the amino acid proline). A better understanding of the social deficits of 22q11.2 DS adolescents with ASD will be essential for the future design of targeted behavioral interventions. Increased insight into the genetic variants and white matter pathology associated with ASD could aid the early identification of high-risk patients and allow for targeted preventive treatments.