Cornelia de Lange Syndrome (CdLS) is a multisystem genetic disorder caused by mutations in the cohesin complex. It is believed that cohesin is able to regulate gene expression with CTCF by holding chromatin in topological complexes, such as active chromatin hubs, and that CdLS is caused by loss of these complexes causing aberrant gene expression. In order to determine if loss of these complexes in CdLS resulted in a general change in the compaction of chromatin, I undertook a series of analyses of the nucleus in CdLS patient lymphoblastoid cell lines (LCLs), compared to wildtype, and later in RNAi knockdown models of CdLS. By fluorescent in situ hybridisation (FISH) I studied the chromatin compaction of different regions of the genome, and found that in some, but not all, CdLS cell lines, gene-rich regions have less compact chromatin compared to wildtype. RNAi knockdown of two proteins that are mutated in CdLS, NIPBL and SMC1, also resulted in decompaction of regions of the genome, however these were different regions than in the patient LCLs, perhaps due to variation between cell lines. This change was not due to the interaction between cohesin and CTCF, as I found that knockdown of CTCF did not result in changes in chromatin compaction. I have also looked at the published data for gene expression in CdLS, and in mouse and Drosophila models of CdLS, and have found no correlation between the genes misexpressed in CdLS in the three species, nor between three cell lines of the same species. These data suggest that the variation in chromatin compaction observed in CdLS may not be due to an interaction between cohesin and CTCF, and that cohesin can act independently of CTCF to regulate gene expression.

Congenital microcephaly (conMiC) is a manifestation of severely disrupted prenatal brain development, caused by genetic defects, toxins, severe maternal malnutrition, or infection. The Zika virus outbreak and the devastating impact of Zika infection on the fetal brain have focused much attention on the cellular and molecular pathophysiology of conMiC. Mendelian conMiC disorders offer a unique opportunity for understanding gene and protein networks that direct cellular processes essential for prenatal brain development. Using OMIM and literature searches, I analyzed 68 conMiC disorders and their 65 corresponding genes. ConMiC-disorder phenotypes were characterized by analyzing the co-occurrence of ID, retinal abnormalities, seizures, and short stature. Short stature co-occurred with 70% of conMiC disorders, while seizures and retinopathy co-occurred with 68% and 37%, respectively. In 53% of conMiC disorders, seizures and short stature overlapped, while all features overlapped in 22% of conMiC disorders; only 7% of conMiC disorders lacked one of these co-occurring features. This shows conMiC genes are rarely specialized for brain growth, with generalized functions in overall body growth, retinal development, and/or regulation of neural activity. ConMiC-gene transcript accumulation in the brain is typically greatest during the prenatal period, and then declines postnatally, suggesting active transcriptional repression. Nonetheless, in neurons and glia of the adult brain, 44 conMiC genes had confirmed persistent protein accumulation. Experimental evidence indicates transcription in neural progenitor cells (NPCs) for at least 82% of conMiC genes. The spatiotemporal expression patterns of conMiC genes tend to align well with their biological functions and corresponding mutant phenotypes. Nearly 60% of conMiC gene products have functions in the cell cycle and/or DNA repair. Most conMiC disorders are caused by recessive, loss-of-function mutations. There are direct binding and regulatory interactions amongst many conMiC genes, which interact in larger networks and shared pathways. Depletion of single conMiC gene products can affect the transcript and/or protein levels of other conMiC gene products, which could have a “domino effect”, and disrupt entire networks important for brain development. Further evidence for this model is that 22 conMiC genes are consistently dysregulated in Zika-infected developing human brain tissue. Due to the complexity of conMiC genes and their interactions, there are many unique challenges to developing treatments for conMiC, particularly conMiC caused by maternal Zika-virus infection. However, insights to treatment strategies could be gained by using human genetics to find potential modifiers, screening for drugs that can normalize disrupted cell cycle and DNA-repair processes, or can stabilize protein complexes that are disrupted due to a conMiC gene mutation.

The prevalence of Autism Spectrum Disorder (ASD) and its defining features has been increasingly investigated in genetic syndromes associated with intellectual disability, with syndrome specific profiles reported. The experience of catatonia and other movement disorders in people with ASD has been increasing highlighted within both research and diagnostic guidelines. However, these issues have not typically been investigated alongside other features of ASD within research into genetic syndromes. The first paper in this thesis provides a review of the literature on movement disorders in genetic syndromes associated with ASD, which focuses on the prevalence of reported movement disorders, the methods of assessment used, and the quality of research to date. An empirical study is reported in Paper 2. Within a cohort of individuals with Cornelia de Lange and Fragile X syndromes the prevalence of attenuated behaviour [autistic catatonia] is examined, based on parent/carer report, and the extent to which features of ASD predict later attenuated behaviour is investigated. Paper 3 provides a critical reflection on the first two papers as well as some wider considerations on undertaking research in this area. The results of both the literature review and the empirical study indicated that across a number of genetic syndromes (Angelman syndrome, Cornelia de Lange syndrome, Fragile X syndrome and Rett syndrome) attenuated behaviour [autistic catatonia] and/or movement disorders affect a substantial proportion of individuals. Furthermore, repetitive behaviours, one of the characteristic features of ASD, appear to predict later attenuated behaviour in Cornelia de Lange and Fragile X syndromesThe results presented in this thesis have important implications for the way services support individuals with specific genetic syndromes. Paper 1 confirms the high prevalence of movement problems in Angelman and Rett syndromes, and Paper 2 provides a new insight into movement problems in Cornelia de Lange and Fragile X syndromes. Movement disorders are reported to impact negatively on wellbeing and quality of life in people with ASD, and are likely to have a similar impact on the lives of people with genetic syndromes. Greater awareness and recognition of movement problems in CdLS and FXS is required, and although specialist services may already be aware of some of the above issues, there should be an increased emphasis on ensuring that community services are aware of the needs of individuals with genetic syndromes, including the implications of movement problems for support needs and quality of life.

A linguagem e a comunicação são processos fundamentais para o desenvolvimento humano. Mas longe de serem processos inatos ou maturacionais são processos sócio-históricos que se desenvolvem ao longo da vida. Dessa forma, quando as crianças chegam à idade escolar trazem com elas uma linguagem e comunicação oral não como produtos acabados, mas como processos sociais e em desenvolvimento Professores de séries iniciais muitas vezes são surpreendidos quando uma criança não fala, ficando sem ação, pois a expectativa deles é trabalhar apenas com a escrita. Eles pressupõem que oralidade já deveria estar desenvolvida em seus alunos. A escola tem papel fundamental nesse processo de alfabetização, mas também no desenvolvimento da linguagem como um todo incluindo as diversas formas de comunicação possíveis, pois, é de suma importância que a escola acolha todas as pessoas sem discriminações ou preconceitos. Esta pesquisa teve como foco principal propor ações mediadoras com uso de recursos e estratégias de CAA para promover o desenvolvimento da comunicação em sujeitos com TGD. As ações mediadoras foram embasadas nos pressupostos da Teoria Sócio-Histórica, focando em estratégias nas quais a interação vise à comunicação com recursos de CAA de baixa e alta tecnologia como foco principal. O presente trabalho estruturou-se como um estudo de caso (multicaso) de dois sujeitos incluídos nas séries iniciais do ensino fundamental na rede publica municipal da grande Porto Alegre. Ambos os sujeitos tem TGD, sendo que um tem diagnóstico de autismo e o outro de Síndrome de Cornélia de Lange (CdLS). Os resultados a serem apresentados mostram que é possível a utilização da CAA no processo do desenvolvimento de sujeitos não oralizados com TGD, pois, de forma geral, percebe-se que no final da pesquisa os sujeitos ampliaram suas formas de comunicação graças ao uso da CAA. Os indícios de intencionalidade de comunicação que emergiram nos sujeitos com TGD, quando utilizadas ações mediadoras com CAA, se ampliaram de forma significativa chegando os sujeitos a tornarem-se agentes intencionais em diversos momentos das interações. / Language and communication are key processes in human development. But far from being innate or maturational processes, they are socio-historical processes that develop throughout life. Thus, when children reach school age they bring with them the language and oral communication not as a finished product, but as a social process in development. Schoolteachers are often surprised when a child does not speak, and do not know what to do, because their expectation is to work only with writing. They assume that orality should have been already developed in their students. The school has a fundamental role in the process of literacy, but also in language development as a whole, including the various forms of possible communication. Therefore, it is essential that the school accepts all persons without discrimination or prejudice. This research aims to propose mediation actions through the use of resources and strategies of AAC to promote the communication development in subjects with PDD. The mediating actions were based on the principles of the Social-Historical Theory, focusing on strategies in which the interaction aimed at communicating with AAC features of low and high technology. This study was structured as a case study (multicase) of two individuals inserted in the initial grades of elementary public school at Porto Alegre. Both subjects have PDD; one was diagnosed with autism and the other with Cornelia de Lange Syndrome (CdLS). The results presented show that it is possible to use the AAC in the development process of individuals with PDD and with oral language issues because, in general, at the end of the study subjects increased their forms of communication through the use of AAC. The evidence of intentional communication that emerged in subjects with PDD when using mediation actions with AAC have expanded significantly, reaching the subjects and turning them into intentional agents at different times of the interactions.

A linguagem e a comunicação são processos fundamentais para o desenvolvimento humano. Mas longe de serem processos inatos ou maturacionais são processos sócio-históricos que se desenvolvem ao longo da vida. Dessa forma, quando as crianças chegam à idade escolar trazem com elas uma linguagem e comunicação oral não como produtos acabados, mas como processos sociais e em desenvolvimento Professores de séries iniciais muitas vezes são surpreendidos quando uma criança não fala, ficando sem ação, pois a expectativa deles é trabalhar apenas com a escrita. Eles pressupõem que oralidade já deveria estar desenvolvida em seus alunos. A escola tem papel fundamental nesse processo de alfabetização, mas também no desenvolvimento da linguagem como um todo incluindo as diversas formas de comunicação possíveis, pois, é de suma importância que a escola acolha todas as pessoas sem discriminações ou preconceitos. Esta pesquisa teve como foco principal propor ações mediadoras com uso de recursos e estratégias de CAA para promover o desenvolvimento da comunicação em sujeitos com TGD. As ações mediadoras foram embasadas nos pressupostos da Teoria Sócio-Histórica, focando em estratégias nas quais a interação vise à comunicação com recursos de CAA de baixa e alta tecnologia como foco principal. O presente trabalho estruturou-se como um estudo de caso (multicaso) de dois sujeitos incluídos nas séries iniciais do ensino fundamental na rede publica municipal da grande Porto Alegre. Ambos os sujeitos tem TGD, sendo que um tem diagnóstico de autismo e o outro de Síndrome de Cornélia de Lange (CdLS). Os resultados a serem apresentados mostram que é possível a utilização da CAA no processo do desenvolvimento de sujeitos não oralizados com TGD, pois, de forma geral, percebe-se que no final da pesquisa os sujeitos ampliaram suas formas de comunicação graças ao uso da CAA. Os indícios de intencionalidade de comunicação que emergiram nos sujeitos com TGD, quando utilizadas ações mediadoras com CAA, se ampliaram de forma significativa chegando os sujeitos a tornarem-se agentes intencionais em diversos momentos das interações. / Language and communication are key processes in human development. But far from being innate or maturational processes, they are socio-historical processes that develop throughout life. Thus, when children reach school age they bring with them the language and oral communication not as a finished product, but as a social process in development. Schoolteachers are often surprised when a child does not speak, and do not know what to do, because their expectation is to work only with writing. They assume that orality should have been already developed in their students. The school has a fundamental role in the process of literacy, but also in language development as a whole, including the various forms of possible communication. Therefore, it is essential that the school accepts all persons without discrimination or prejudice. This research aims to propose mediation actions through the use of resources and strategies of AAC to promote the communication development in subjects with PDD. The mediating actions were based on the principles of the Social-Historical Theory, focusing on strategies in which the interaction aimed at communicating with AAC features of low and high technology. This study was structured as a case study (multicase) of two individuals inserted in the initial grades of elementary public school at Porto Alegre. Both subjects have PDD; one was diagnosed with autism and the other with Cornelia de Lange Syndrome (CdLS). The results presented show that it is possible to use the AAC in the development process of individuals with PDD and with oral language issues because, in general, at the end of the study subjects increased their forms of communication through the use of AAC. The evidence of intentional communication that emerged in subjects with PDD when using mediation actions with AAC have expanded significantly, reaching the subjects and turning them into intentional agents at different times of the interactions.

A linguagem e a comunicação são processos fundamentais para o desenvolvimento humano. Mas longe de serem processos inatos ou maturacionais são processos sócio-históricos que se desenvolvem ao longo da vida. Dessa forma, quando as crianças chegam à idade escolar trazem com elas uma linguagem e comunicação oral não como produtos acabados, mas como processos sociais e em desenvolvimento Professores de séries iniciais muitas vezes são surpreendidos quando uma criança não fala, ficando sem ação, pois a expectativa deles é trabalhar apenas com a escrita. Eles pressupõem que oralidade já deveria estar desenvolvida em seus alunos. A escola tem papel fundamental nesse processo de alfabetização, mas também no desenvolvimento da linguagem como um todo incluindo as diversas formas de comunicação possíveis, pois, é de suma importância que a escola acolha todas as pessoas sem discriminações ou preconceitos. Esta pesquisa teve como foco principal propor ações mediadoras com uso de recursos e estratégias de CAA para promover o desenvolvimento da comunicação em sujeitos com TGD. As ações mediadoras foram embasadas nos pressupostos da Teoria Sócio-Histórica, focando em estratégias nas quais a interação vise à comunicação com recursos de CAA de baixa e alta tecnologia como foco principal. O presente trabalho estruturou-se como um estudo de caso (multicaso) de dois sujeitos incluídos nas séries iniciais do ensino fundamental na rede publica municipal da grande Porto Alegre. Ambos os sujeitos tem TGD, sendo que um tem diagnóstico de autismo e o outro de Síndrome de Cornélia de Lange (CdLS). Os resultados a serem apresentados mostram que é possível a utilização da CAA no processo do desenvolvimento de sujeitos não oralizados com TGD, pois, de forma geral, percebe-se que no final da pesquisa os sujeitos ampliaram suas formas de comunicação graças ao uso da CAA. Os indícios de intencionalidade de comunicação que emergiram nos sujeitos com TGD, quando utilizadas ações mediadoras com CAA, se ampliaram de forma significativa chegando os sujeitos a tornarem-se agentes intencionais em diversos momentos das interações. / Language and communication are key processes in human development. But far from being innate or maturational processes, they are socio-historical processes that develop throughout life. Thus, when children reach school age they bring with them the language and oral communication not as a finished product, but as a social process in development. Schoolteachers are often surprised when a child does not speak, and do not know what to do, because their expectation is to work only with writing. They assume that orality should have been already developed in their students. The school has a fundamental role in the process of literacy, but also in language development as a whole, including the various forms of possible communication. Therefore, it is essential that the school accepts all persons without discrimination or prejudice. This research aims to propose mediation actions through the use of resources and strategies of AAC to promote the communication development in subjects with PDD. The mediating actions were based on the principles of the Social-Historical Theory, focusing on strategies in which the interaction aimed at communicating with AAC features of low and high technology. This study was structured as a case study (multicase) of two individuals inserted in the initial grades of elementary public school at Porto Alegre. Both subjects have PDD; one was diagnosed with autism and the other with Cornelia de Lange Syndrome (CdLS). The results presented show that it is possible to use the AAC in the development process of individuals with PDD and with oral language issues because, in general, at the end of the study subjects increased their forms of communication through the use of AAC. The evidence of intentional communication that emerged in subjects with PDD when using mediation actions with AAC have expanded significantly, reaching the subjects and turning them into intentional agents at different times of the interactions.