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Genomic Approach in Idiopathic Intellectual Disability Maria De Fátima E Costa Torres

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Genomic Approach in Idiopathic Intellectual Disability Maria De Fátima E Costa Torres ESTUDOS DE 8 01 PDPGM 2 CICLO Genomic approach in idiopathic intellectual disability Maria de Fátima e Costa Torres D Autor. Maria de Fátima e Costa Torres D.ICBAS 2018 Genomic approach in idiopathic intellectual disability Genomic approach in idiopathic intellectual disability Maria de Fátima e Costa Torres SEDE ADMINISTRATIVA INSTITUTO DE CIÊNCIAS BIOMÉDICAS ABEL SALAZAR FACULDADE DE MEDICINA MARIA DE FÁTIMA E COSTA TORRES GENOMIC APPROACH IN IDIOPATHIC INTELLECTUAL DISABILITY Tese de Candidatura ao grau de Doutor em Patologia e Genética Molecular, submetida ao Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto Orientadora – Doutora Patrícia Espinheira de Sá Maciel Categoria – Professora Associada Afiliação – Escola de Medicina e Ciências da Saúde da Universidade do Minho Coorientadora – Doutora Maria da Purificação Valenzuela Sampaio Tavares Categoria – Professora Catedrática Afiliação – Faculdade de Medicina Dentária da Universidade do Porto Coorientadora – Doutora Filipa Abreu Gomes de Carvalho Categoria – Professora Auxiliar com Agregação Afiliação – Faculdade de Medicina da Universidade do Porto DECLARAÇÃO Dissertação/Tese Identificação do autor Nome completo _Maria de Fátima e Costa Torres_ N.º de identificação civil _07718822 N.º de estudante __ 198600524___ Email institucional [email protected] OU: [email protected] _ Email alternativo [email protected] _ Tlf/Tlm _918197020_ Ciclo de estudos (Mestrado/Doutoramento) _Patologia e Genética Molecular__ Faculdade/Instituto _Instituto de Ciências Biomédicas de Abel Salazar_ Identificação da publicação X Dissertação de mestrado Tese de doutoramento Título completo _Abordagem genómica no atraso mental idiopático /Genomic approach in idiopathic intelectual disability_ Orientador _Patrícia Espinheira de Sá Maciel_ Coorientador(es) _Maria da Purificação Valenzuela Sampaio Tavares e Filipa Abreu Gomes de Carvalho Data da conclusão (defesa pública) _11 de Junho de 2019 Especialidade /Ramo de Conhecimento __Genética _ Palavras-chave _Perturbações do neurodesenvolvimento_; défice intelectual_; _epilepsia_; __aCGH__; _WES_ Declaro, sob compromisso de honra, que xX O exemplar da publicação corresponde à versão final aprovada pelo júri Autorizo a disponibilização imediata do texto integral no Repositório da U.Porto Autorizo a disponibilização do texto integral no Repositório da U.Porto no prazo de: 6 Meses X 12 Meses Justificação para a não autorização imediata _Há estudos ainda em curso que se prevê serem finalizados e publicados no decorrer do próximo ano Mantenho todos os direitos de uso em trabalhos futuros. Data ____________________ Assinatura _______________________________________________________________________________________________ II Aos meus pais e à minha família, por tudo; ao meu pai, que nos deixou a 19-02-2018. III Agradecimentos Há um provérbio Africano que diz: "Se queres ir depressa, vai sozinho. Se queres ir longe, vai acompanhado ". Seria impossível ter realizado todo este trabalho, condensado agora nesta tese, sem o contributo e o apoio de várias pessoas a quem gostaria de agradecer publicamente: À Professora Doutora Patrícia Maciel, por ter aceite orientar este trabalho, mesmo sendo eu uma outsider da Universidade do Minho. Patrícia, muito obrigada por todo o trabalho extra (reuniões, discussões, artigos, telefonemas e emails) que tiveste durante estes anos! Foi um prazer trabalhar contigo e participar ao longo deste tempo nos vários projetos que conduziram a esta tese! À Professora Doutora Purificação Tavares, pela disponibilidade demonstrada, quer pessoal, ao ser coorientadora do trabalho, quer institucional, ao disponibilizar o uso de dados do CGC para serem usados como base deste trabalho. À Professora Doutora Filipa Carvalho, pela disponibilidade demonstrada na coorientação deste trabalho e pelo apoio dado ao longo deste percurso. À Fátima L., pelas muitas experiências, reuniões, discussões, artigos, telefonemas e emails que partilhámos, tanto nos trabalhos de aCGH como no estudo de epilepsia/WES: muito obrigada por tudo, e em particular pelas tuas providenciais fórmulas nas folhas de Excel e pela ajuda nesta fase final com os dados de WES. Foi um prazer trabalhar contigo e espero que o contacto se mantenha. Desejo-te muitas felicidades e o maior sucesso para a tua vida, pessoal e profissional. À Dra. Paula Rendeiro, Directora do Laboratório de Citogenética do CGC, pela colaboração e partilha de dados de aCGH, bem como pela contribuição na realização de análises suplementares de FISH, que serviram de complemento a alguns casos. IV Ao Dr. Jorge Pinto-Basto, Director do Laboratório de Diagnóstico Molecular e Genómica Clínica do CGC, por ter possibilitado a realização de extrações de DNA/RNA para além, nesta fase final do trabalho, das sequenciações de Sanger necessárias à complementação de certos estudos. A todos os colegas do CGC que de alguma forma contribuíram para este trabalho, em particular: - À equipa da ARCA, por todos os registos extra que fizeram; - À equipa da EXTRACÇÃO (Catarina Ribeiro, Marta e Aleksandra), pelas amostras adicionais de DNA e RNA que processaram; - Aos colegas “voluntários” que contribuíram com colheitas de sangue para os estudos de expressão (Cláudia, Catarina Varela, Diana, Sara Teixeira, Cristiano, Marcos, Paulo Brochado), bem como à Ana Paula e à Clara, que fizeram as colheitas; - Às meninas que trabalham diretamente comigo (Alexandra Lopes, Liliana Gonçalves, Lígia Lameiras, Carolina e, também, à Inês Eulálio): muito obrigada pelo interesse e pelo apoio demonstrados; um agradecimento especial à Carolina, pela ajuda nesta fase final, com as sequenciações de Sanger. E, last but not the least , à minha enorme família e aos meus (também enormes) amigos, por todo o apoio e amizade! O meu muito obrigada a todos! V Abstract Neurodevelopmental disorders (NDs) are a large group of clinical entities caused by the disruption of brain development, that impact personal, social, academic and occupational functioning. Intellectual disability (ID), formerly referred to as mental retardation, is one of the most common NDs, affecting nearly 1-3% of the world population, with onset in infancy or in the early childhood, being characterized by significant limitations both in intellectual functioning and in adaptive behavior as expressed in conceptual, social and practical adaptive skills. Epilepsies are common complex neurological diseases, characterized by recurrent (two or more) spontaneous seizures, that constitute the third leading contributor to the global burden of disease for neurological disorders. Epilepsy is a frequent feature of NDs, being commonly associated with ID. The etiology of NDs, in general, and of ID and epilepsy, in particular, is complex and often results from the combination of environmental or acquired (non-genetic) and genetic factors. Genetic causes are thought to be responsible for 17-50% of the cases of ID, while in about 70% of the epilepsy cases, genetic factors play a major role, polygenic cases being predominant. Both epilepsy and ID represent a major burden not only for the individual, but also to his/her immediate family. Being so, the clarification of etiology is important to provide information regarding prognosis or expected clinical course, being fundamental to guide an adequate intervention. The determination of the precise molecular cause (genotype) that explains the clinical features of a particular disease (phenotype) may be a considerable challenge, either due to an incomplete knowledge about a particular disease or due to the variability associated with certain conditions. However, the rapid development in genetic tools and sequencing technology in the past few years had a particular impact in the understanding of the genetics of NDs. Advances in chromosomal microarray technology have allowed for the analysis of copy number variations (CNVs) in very large case–control cohorts and highlighted the biological relevance of these structural variants. On the other hand, the great advances of massive parallel sequencing (MPS) technologies expanded the sequencing coverage of the genome and potentiated the capacity to identify variants that explain many Mendelian diseases in both known and novel disease genes. VI In this work, we have used both aCGH and MPS techniques in order to unravel the genetic etiology of neurodevelopmental disease in a large series of patients of Portuguese origin. aCGH was performed in a large group of patients with idiopathic ID and in a large family with epilepsy, while WES analysis was performed in selected patients from this group. These techniques were complemented, whenever necessary, with quantitative polymerase chain reaction (qPCR) and qRT-PCR or RT-PCR plus Sanger sequencing. With this approach, we were able to identify pathogenic or likely pathogenic causal variants in 13.2% of the patients of the ID group, and to pinpoint 12 new candidate loci for ID. Moreover, we confirmed the AKT3 gene as a key gene for microcephaly, although recognizing the role of other factors in the manifestation of the phenotype. We showed that microduplications in the 2p15p16.1 region, although rare, are consistently associated with ID and specific morphological anomalies. We have proposed the CALD1 gene as the most likely candidate for the core phenotype (i.e. ID and behavioral alterations) associated with small CNVs at 7q33 region. We have observed an increased expression consistent with the change in copy number in several genes within duplications
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