We continue to refine the differential diagnosis of this rare but devastating condition. The best indicator of true disorder compared to pediatric bipolar and depressive disorder is the extreme severity of psychotic symptoms (Gochman et al 2011). In comparison with adult patients, childhood onset patients have a greater number of different modalities of hallucination which appear additive in nature and which are associated with greater intellectual impairment suggesting that these are measures of abnormal cortical brain connectivity (David et al 2011). Cognitive studies have begun within this protocol to obtain prospective measures of working memory and attention for young full siblings of the childhood onset schizophrenia patients. It is hypothesized that earlier cognitive relative deficits will be ameliorated in parallel with temporal and frontal cortical brain/development. Our prospective studies of normal and abnormal brain development have greatly influenced the fields of pediatric neurology, child psychology and pediatrics (Giedd &Rapoport, 2010). Ongoing brain imaging studies find that in a second independent sample, that healthy full siblings have early frontal and temporal cortical brain thinning which normalizes by mid adolescence (Mattai et al 2011). This may represent a healthy phenotype for future genetic studies. Studies of anatomic hippocampal development in the healthy siblings showed no deviance from that seen for the healthy controls indicating that hippocampal abnormalities may be disease related and not genetic markers. Follow up studies in collaboration with the University of Chicago (Dr. Czernansky) are examining hippocampal shape to complete this investigation. Non-psychotic individuals at increased risk for schizophrenia show alterations in fronto-striatal dopamine signaling and cortical gray matter maturation reminiscent of those seen in schizophrenia. We sought to address these issues by relating a functional Val-->Met polymorphism within the gene encoding catechol-o-methyltransferase (COMT)-a key enzymatic regulator of cortical dopamine levels-to longitudinal structural neuroimaging measures of cortical dopamine levels to longitudinal structural neuroimaging measures of cortical gray matter thickness. Brain MRI scans, acquired between 9 and 22 years from patients with childhood-onset schizophrenia (COS), their non-psychotic full siblings, and matched healthy controls were compared. Val allele dose (which confers enhanced dopamine catabolism and is proposed to aggravate cortical deficits in schizophrenia) accelerated adolescent cortical thinning in both schizophrenia probands and their siblings, but lesser cortical thinning in healthy controls. These findings suggest that cortical abnormalities in pedigrees affected by schizophrenia may be contributed to by a disruption of dopaminergic influences on cortical maturation. Several genetic studies are ongoing. Individual case studies from our cohort indicate that exome sequencing studies are likely to be informative as we are already finding unique variants in selected cases e.g. Addington et al 2011, Anderson et al in press, Lee et al in press. To better understand the heritability of schizophrenia, and to identify de novo gene mutations, collaborators at the University of Montreal (Dr. Guy Roulleau) are conducting targeted sequencing of 5,000 brain development-related genes from 30 trios, comprising affected children with schizophrenia and their parents. Using the trios, we are also probing rare variants that may be associated with the disease. Finally, a collaborative study with Drs. Kristin Brennand and Fred Gage of the Salk Institute is studying development of neuronal connectivity and neurite number from iPS derived neurons from our childhood onset schizophrenia patients. Patients with and without rare disease associated copy number variants (CNVs) are included. Contrast groups will include unrelated healthy controls, healthy and affected family members who are carriers of risk CNVs.