This work is conducted under protocol 89-M-0006 (NCT00001246), and falls into two broad research themes: Theme 1: Studies of behavior and brain organization in typically-developing groups Work in this theme uses large-scale neuroimaging studies in health to advance our basic understanding of human brain organization, and guide the selection and application of imaging phenotypes for disease studies. We have so far emphasized structural magnetic resonance imaging (sMRI) because it offers intermediate in vivo phenotypes that can be reliably measured at scale, and are highly heritable, developmentally dynamic, sensitive to disease states, and amenable to translational study in mice. During the last year, we have published work in three main areas. First, we have used brain scans from groups of related individuals to better understand genetic control of brain development and how these influences overlap with genetic determinants of cognitive ability. Second, in a large sample of typically-developing youth, we have identified aspects of brain anatomy that correlate with inter-individual variation in childhood socioeconomic status and cognitive ability. Third, we have generated fine-grained maps of differences in subcortical anatomy between typically developing males and females. As genetic variation, environmental factors, cognitive ability, and gender all play critical roles in shaping mental health during development these studies reveal brain systems that we can prioritize for further analysis in patient groups. Theme 2: Deep phenotypic studies of participants with sex chromosome aneuploidy syndromes (SCAs) Work in this theme seeks to understand brain and behavioral changes in individuals with genetically defined neurodevelopmental disorders focusing on sex chromosome aneuploidy syndromes (SCAs) in particular. Collectively, these studies are designed to expand on past work in SCA by gathering more comprehensive measures of brain structure and function, as well as providing more fine-grained information regarding the cognitive and behavioral variations that can be seen in SCA. These data will ultimately help to better define the developmental risks and resiliencies associated with X- and Y-chromosome dosage variation in humans, and identify neurobiological systems that might underpin these associations. We hope these insights will (i) improve accurate public and professional awareness of SCAs, (ii) help clinicians provide more targeted assessment and counseling to patients and families with SCA, and (iii) begin to identify biological markers with the potential to ultimately improve assessment, prediction and treatment of neurodevelopmental issues in SCA. More broadly, this work in the specific case of SCA will shed light on (i) the principles that organize genetic influences on brain and behavior in the context of neuropsychiatric impairment, and (ii) genetic contributions to sex-differences in the brain, which are relevant for understanding the well-documented male-bias in risk for neurodevelopmental disorders more generally. During the last year, we have published work in three main areas. First, we have provided the most detailed characterization of changes in cognition and autism risk associated with XYY syndrome. Second, we have used in vivo structural neuroimaging to detail how variations in X- and Y-chromosome dosage can shape folding of deep gray matter structures in the human brain that regulate memory and emotion processing. Together with our other clinical neuroimaging studies, these findings help to pinpoint when and where genetic causes of neurodevelopmental difficulties can impact brain development. Third, to identify potential molecular bases for observed SCA effects, we have published the first study to systematically examine how X- and Y-chromosome dosage shape genome structure and function in humans. By modeling these effects in tissue from patients, we hope to identify root causes for the changes in brain and behavior that accompany different genetic forms of neurodevelopmental difficulties.