Social communication is important for success at home, school, work, and in the community. Lacking the ability to effectively process and convey information to others can lead to deficits in maintaining personal relationships and academic failure in school. Deficits in social communication skills can include a broad array of verbal and nonverbal behaviors important for reciprocal social interaction. In this dissertation, we are interested in how children use and integrate verbal and multiple channels of non-verbal behaviors in the context of a naturalistic social interaction. To best capture how children communicate during this social interaction, we have devised a micro-analytic coding scheme that will reveal which channels children use to convey information, as well as how they integrate these different channels. In the following studies, different components of communication will be assessed in individuals with typical development and children with neurodevelopmental disorders of different natures and origins. Our groups include: Typically Developing (TD) children, children with High Functioning Autism (HFA), children with Williams Syndrome (WS), and children with Perinatal Stroke (PS). The majority of research regarding communication in these groups has focused on infants, toddlers, and younger pre- school children, before the children are proficient language users. In studying school age children, we can determine how communication is distributed across multiple communicative channels, now that language has become their primary communicative system. Studying TD children can provide a greater understanding of the range and nature of typical development and can help identify and create more appropriate therapeutic interventions for individuals exhibiting abnormal social and emotional behaviors. Individuals with neurodevelopmental disorders often have significant impairments in social communication that impact their relationships with others. In Chapter 2, a literature review on the communicative behaviors regarding each of our groups of children is presented. Chapter 3 is devoted to an investigation of social communication in TD school age children. Chapter 4 focuses on the social and affective components of communication in children with HFA and children with WS. Chapter 5 investigates the use and integration of language and emotional expression in school age children with PS. These studies make a significant contribution toward understanding the interrelationships of the social and affective components of communication in school age children

Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.