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Universidade de Aveiro Departamento de Química Ano 2011 Fátima Daniela Alterações de dosagem no genoma de doentes com Teixeira Lopes atraso mental Genomic imbalances in patients with intellectual disability Universidade de Aveiro Departamento de Química Ano 2011 Fátima Daniela Alterações de dosagem no genoma de doentes Teixeira Lopes com atraso mental Genomic imbalances in patients with intellectual disability Dissertação apresentada à Universidade de Aveiro para cumprimento dos requisitos necessários à obtenção do grau de Mestre em Biotecnologia , realizada sob a orientação científica da Doutor a Patrícia Espinheira de Sá Maciel, Professora A uxiliar da Escola de Ciências da Saúde da Universidade do Minho, e da Doutora Odete Cruz e Silva, Professora A uxiliar do Departamento de Biologia da Universidade de Aveiro. Apoio financeiro da FCT (PIC/IC/83026/2007) no âmbito do III Quadro Comunitário de Apoio. “Sooner or later we will find the cause, and it will be in exactly the same way as we have found genes for other disorders - by lucky coincidence. (…)There isn't anything unique about not having discovered it yet." John Marius Opitz, 1997 Por este motivo, este pequeno contributo é dedicado aos pais das crianças envolvidas neste estudo. o júri presidente Professor Doutor Jorge Manuel Alexandre Saraiva Investigador Auxiliar do Departamento de Química da Universidade de Aveiro Professora Doutora Filipa Abreu Gomes de Carvalho Professora Associada com Agregação da Faculdade de Medicina da Universidade do Porto Professora Doutora Patrícia Espinheira de Sá Maciel Professora Auxiliar da Escola de Ciências da Saúde da Universidade do Minho Professora Doutora Odete Cruz e Silva Professora Auxiliar do Departamento de Biologia da Universidade de Aveiro. agradecimentos Em primeiro lugar gostaria de agradecer aos meus pais por estarem sempre ao meu lado e me apoiarem em tudo o que sempre precisei. Ao Albino pelo apoio incondicional, pela paciência, pelo carinho, pela amizade e por acreditar em mim mesmo quando nem eu acredito. À Patrícia pela oportunidade de fazer parte da equipa em primeiro lugar, pelo voto de confiança na realização deste trabalho, pela oportunidade de realizar o mestrado em conjunto com as minhas funções no ICVS e pela sua orientação. Sinceramente muito obrigada! Ao doutor Jorge Saraiva e ao doutor João Coutinho por me terem recebido como aluna do mestrado em Biotecnologia. A todos os elementos do ICVS, em particular aos NeRDs. Aos meus colegas de laboratório em especial: à Sara, à A. Carvalho, à Anabela, à Ana João, à A. Castro, à Sofia M., à Sofia L., à Sandra e à Susana por toda a ajuda quando precisei, por todos os con selhos acertados que me deram. To my colleagues at MAF in VU Medical Center, in particular to doctor Bau ke Ylstra for receiving me in his laboratory. A todos os elementos do projecto dos aCGH e do XLMR, assim como à FCT pelo financiamento. palavras -chave Atraso do desenvolvimento; Atraso mental; aCGH; Alterações do número de cópias resumo O atraso mental (AM) é uma doença que apresenta desafios para a vida tanto nas famílias como na sociedade. É caracterizada por um funcionamento sub- óptimo do sistema nervoso central que manifesta limitações quer ao nível da capacidade intelectual quer do comportamento adaptativo e tem uma incidência de aproximadamente 2-3% de nados vivos em todo o mundo. A determinação da causa da doença é importante para o correcto encaminham ento clínico, aconselhamento genético e estratégias de coping a desenvolver pela família. A técnica de hibridação genómica comparativa (aCGH), também designada de cariótipo molecular (CM), permite medir variações no número de cópias entre o genoma do doent e e de um controlo. A totalidade do genoma de um indivíduo é representado num cariótipo virtual de alta resolução, permitindo assim a detecção de alterações submicroscópicas indetectáveis por métodos de cariotipaem standard ou de alta resolução. Em Portug al, as recomendações para os testes genéticos a realizar num doente com AM indicam o cariótipo tradicional de bandas G como primeira abordagem e, sempre que o resultado seja negativo, a pesquisa relativa às patologias unigénicas mais comuns (Síndrome de X frágil, por exemplo), rearranjos subteloméricos e sondas de FISH específicas. No entanto, estas tecnologias não são aplicáveis para análise de todo o genoma no contexto de diagnóstico de rotina, tanto pela sua baixa resolução (caso do cariítpo convencional) como pela elevada laboriosidade e/ou custos monetários (caso do FISH). A introdução de aCGH pretende contribuir para a classificação etiológica de grande parte dos doentes com AM, assim como, concluir acerca da utilidade desta tecnologia para o diagnóstico de AM idiopático no contexto clínico. keywords Development delay; Intellectual disability; aCGH; Copy number variations abstract Development delay/Intellectual disability (DD/ID) is a serious and life-long condition which represents a challenge for families and public health services. It is characterized by suboptimal functioning of the central nervous system resulting in limitation s both in intellectual functioning and in adaptive behavior, and it is observed in approximately 2-3% of the population worldwide. Establishing the disease etiology is important for clinical management, genetic counseling and coping strategies of the families. Array-based comparative genomic hybridization technique (aCGH), also called molecular karyotyping (MC), allows us to directly measure genomic copy number variations between the patient and a control DNA. The whole genome of an individual is represented in a high-resolution “virtual karyotype”, allowing the detection of submicroscopic alterations, undetectable by standard or high- resolution karyotyping techniques. In Portugal, the guidelines for testing patients with DD/ID indicate the G- banding karyotyping in first place and, whenever the result is normal , testing for the most common single gene disorders (Fragile X, for instance), for subtelomeric rearrangements and with specific FISH probes. However, the latter technologies are not suitable for whole genome scans in routine diagnosis, both because of the lower resolution levels (the case of conventional karyotyping), the extensive time consumption and high costs (the FISH case). The introduction of aCGH should contribute to the etiological classificat ion of a large proportion of the DD/ID patients as well as to conclude about the utility of using these technologies for diagnosis of idiopathic DD/ID in the clinical context. Publicações Comunicações Orais Mafalda Barbosa, Maria João Sá, Cristina Dias, João Silva, Ana Maria Fortuna, Fátima Lopes , Patrícia Maciel, Hanna Verdin, Elfride de Baere, Eduardo Silva, Gabriela Soares “FOXL2 mutations: from 1 base pair to 10 Megabase ”. 14ª Reunião da Sociedade Portuguesa de Genética Humana. Coimbra; 18-20 Novembro de 2010; Comunicação oral. João Silva, Fátima Lopes , Gabriela Soares, Mafalda Barbosa, Miguel Rocha, Gisela Barros, Catarina Gomes, Teresa Temudo, Bauke Ylstra, Janneke Weiss, Erik Sistermans, Patrícia Maciel. “aCGH analysis of Portuguese patients with idiopathic mental retardation”. 14ª Reunião da Sociedade Portuguesa de Genética Humana. Coimbra; 18-20 Novembro de 2010; Comunicação oral. Carlos Bessa, Fátima Lopes , Gabriela Soares, João Silva, Mafalda Barbosa, Miguel Rocha, Apresentações em poster Margarida Reis Lima, Ana Maria Fortuna, Frederico Duque, Guiomar Oliveira, Carla Marques, Jorge Pinto-Basto, Gisela Barros, Catarina Gomes, Teresa Temudo, Bauke Ylstra, Janneke Weiss, Erik Sistermans, Patrícia Maciel. “New microdeletion/microduplications detected by aCGH in patients with intelectual disability: seacrh for the key genes ” Conferência Internacional Jerome Lejeune “Genetic intellectual disabilities: progress toward targeted treatments?” Paris 24-26 Março de 2011; Apresentação em poster Fátima Lopes , Henedina Antunes, Gisela Barros, Bauke Ylstra, Janneke Weiss, Erik Sistermans, Patrícia Maciel. “Small 3q29 microduplication covering the genes KIAA0226 and MIR922 in a girl with severe obesity, intelectual disability and microcephaly” . 14ª Reunião da Sociedade Portuguesa de Genética Humana. Coimbra; 18-20 Novembro de 2010; Apresentação em poster. Patrícia Maciel, Anabela Fernandes, Sofia Moura, Fátima Lopes , Sandra Pereira, Bruno Costa , Bauke Ylstra, Janneke Weiss, Teresa Temudo, Teresa Lourenço, José Pedro Vieira. “Variant Rett syndrome in a girl with a pericentric X-chromosome inversion leading to overexpression of the MECP2 gene in the absence of gene duplication ”. 14ª Reunião da Sociedade Portuguesa de Genética Humana. Coimbra; 18-20 Novembro de 2010; Apresentação em poster. Fátima Lopes , Gabriela Soares, João Silva, Mafalda Barbosa, Miguel Rocha, Gisela Barros, Catarina Gomes, Teresa Temudo, Bauke Ylstra, Janneke Weiss, Erik Sistermans, Patrícia Maciel. “aCGH analysis of Portuguese patients with idiopathic mental retardation ”. Conferência Jaques Monod “Mental retardation: from genes to synapses, functions and dysfunctions”, Roscoff, França. Outubro de 2010, Apresentação em poster. Contents List of figures .......................................................................................................................................v List of tables ....................................................................................................................................... ix Abbreviations .....................................................................................................................................
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