We recently completed whole genome screening for copy number variants (CNVs) using Illumina 1M SNP arrays in pediatric patients who were excluded from the COS study for various reasons, as well as all available first degree relatives. There was a wide range of diagnoses among the 82 excluded patients, from bipolar disorder, to OCD, to Tourette Syndrome. Overall, we found that 39 out of the 114 COS patients (34%) carried a rare CNV that is larger than 100kb in size and impacts a known gene. Similarly, 19 out of the 82 ruled out patients (23%) carried a rare CNV, which was not a statistically significant difference compared to the COS patients (p = 0.11). Further, among the rare CNVs identified in the rule out patients, six have recently been reported to be associated with various disorders such as schizophrenia, autism, and intellectual disability, (Addington et al in preparation). In total, we have a higher rate of three distinct CNV regions: 16p11.2 duplication 1, NRXN1 deletions2, and MYT1L duplications 3. This is in addition to our previously reported high rate of sex chromosome abnormalities (7 patients) and 22q11.2 deletions (4 patients). Taken together, these results indicate that specific genetic abnormalities do not associate with disorders based on current diagnostic nosology. More likely, these genetic loci are associated with neurodevelopmental abnormalities which mediate various behavioral disturbances. Further study is warranted to determine the penetrance and pleiotropy of the disease associated loci. In addition to the studies of rare CNVs, we have an ongoing collaboration with Guy Rouleau's lab at Montreal for targeted resequencing of approximately 1000 neurodevelopmental genes. To date, 2 variants have been identified that are likely to be pathogenic: a de novo missense mutation in SHANK34, and a novel frameshift mutation in UPF3B5. These findings will be augmented in the upcoming year as we extend our sequencing studies to include full exome, regulome, and ultimately entire genome. We continue with our efforts to map brain developmental trajectories in COS probands, their healthy siblings, and patients that were ruled out as COS. Healthy siblings share prefrontal and temporal cortical deficits in early ages, but the deficits normalize by late adolescence, a phenomena that we now have replicated (Mattai et al in preparation), and thus suggesting an age specific endophenotype. On the other hand healthy siblings do not share the fixed deficit seen in COS thus suggesting a state dependent phenomena (Mattai et al submitted). Brain imaging studies in children excluded from the childhood schizophrenia study, but with other severe early onset disorders, who do not show evidence of psychosis after inpatient observation, have no cortical thickness abnormalities, while the psychosis NOS (Not Otherwise Specified) patients show milder prefrontal and temporal deficits suggesting a dimensional nature of psychosis. We are currently exploring the neurocircuitry development in COS and sibling populations using resting state and task dependent fMRI and DTI studies in collaboration with researchers at Cambridge, Wayne State, and Johns Hopkins universities. The TDCS treatment trial has so far recruited 13 subjects. The stimulation process appears without any side effects which we are in the process of writing up. The benefits, although encouraging, so far appear marginal in terms of effect size, and we are in the process of proposing an amendment to increase the duration of the cognitive arm of the treatment.
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