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Characterization of a Chromosome Rearrangement Associated with Cardiopathy and Autism”, by Sara Melo Dias

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Characterization of a Chromosome Rearrangement Associated with Cardiopathy and Autism”, by Sara Melo Dias Sara Melo Dias Licenciada em Ciências Biomédicas [Nome completo do autor] [Habilitações Académicas] Characterization of a chromosome rearrangement [Nome completo do autor] associated with cardiopathy and autism [Habilitações Académicas] Dissertação para obtenção do Grau de Mestre em [Nome completo do autor] Genética Molecular e Biomedicina [Habilitações Académicas] Orientador: Doutor Dezsö David, Investigador Auxiliar, Departamento de Dissertação paraGenética obtenção Humana do Grau do de Instituto Mestre emNacional de Saúde Doutor Ricardo [Nome[Engenharia completo Informática]Jorge, do autor] I.P. [Habilitações Académicas] [Nome completo do autor] [Habilitações Académicas] Júri: Presidente: Prof. Doutora Maria Alexandra Núncio de Carvalho Ramos Fernandes [Nome completo do autor] Arguente: Prof. Doutor Pedro Miguel Ribeiro Viana Baptista [Habilitações Académicas] [Nome completo do autor] [Habilitações Académicas] Dezembro de 2017 Dissertação para obtenção do Grau de Mestre em Spine (Lombada) 2017 Characterization of a chromosome rearrangement associated with cardiopathy and autism Sara Melo Dias [Título da Tese] ra ii Júri: Presidente: Prof. Doutora Maria Alexandra Núncio de Carvalho Ramos Fernandes Sara MeloArguente: Dias Prof. Doutor Pedro Viana Baptista Licenciada em Ciências Biomédicas [Nome completo do autor] [Habilitações Académicas] Characterization of a chromosome rearrangement [Nome completo do autor] associated with cardiopathy and autism [Habilitações Académicas] Dissertação para obtenção do Grau de Mestre em [Nome completo do autor] [Título da Tese] Genética Molecular e Biomedicina [Habilitações Académicas] Dissertação para obtenção do Grau de Mestre em [Nome[EngenhariaOrientador: completo Informática] Doutor do autor] Dezsö David, Investigador Auxiliar, Departamento de Genética Humana do Instituto Nacional de Saúde Doutor Ricardo [Habilitações Académicas] Jorge, I.P. [Nome completo do autor] [Habilitações Académicas] Júri: [Nome completoPresidente: do autor]Prof. Doutor a Maria Alexandra Núncio de Carvalho Ramos Fernandes [Habilitações Académicas] Arguente: Prof. Doutor Pedro Miguel Ribeiro Viana Baptista [Nome completo do autor] [Habilitações Académicas] Dezembro de 2017 iii Dissertação para obtenção do Grau de Mestre em iv Identification of candidate gene for Cognitive Deficiencies through characterization of chromosome rearrangements Copyright © Sara Melo Dias, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa. A Faculdade de Ciências e Tecnologia e a Universidade Nova de Lisboa têm o direito, perpétuo e sem limites geográficos, de arquivar e publicar esta dissertação através de exemplares impressos reproduzidos em papel ou de forma digital, ou por qualquer outro meio conhecido ou que venha a ser inventado, e de a divulgar através de repositórios científicos e de admitir a sua cópia e distribuição com objetivos educacionais ou de investigação, não comerciais, desde que seja dado crédito ao autor e editor. v vi Acknowlegments This Project would not have been possible without appropriate authorizations from Doctor Fernando de Almeida and Doctor José Albuquerque, of the Directive Board of Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA, I.P.), and from Doctor Glória Isidro, Coordinator of the Human Genetics Department of INSA, I.P., for which I am extremely grateful. I would like to thank to Doctor David Dezsö to give me the opportunity to preform my master’s thesis in his research group, Genomic Diseases group at Human Genetic Department of INSA, I.P., integrated in the Harvard Medical School-Portugal translational research program project entitled “Citogenética de Próxima Geração Irrompe nos Cuidados de Saúde e contribui para a anotação do Genoma Humano”. And also for all the support, help and advices without which this project would not exist. I would also like to thank to Mariana Marques, Master of Science, and Manuela Cardoso, Master of Science, my “mentors”, for everything. You both guided me through this project, helped when was necessary and for integrating myself in the routines of the laboratory having the patience to teach me the techniques and the places where the things were, without you this would be chaotic. To Joana Fino, Master of Science, for performing the bioinformatics analyses associated to this study, without you none of this would be possible. To Doctor João Freixo for the recruitment of the family in study and for providing all the clinical information needed. To my friends and family for the constant support, for not letting me down, and for helping me to see the light even in the darkest moments. I also want to thank my boyfriend who has been my safe haven at the most difficult times. Thank you all, ___________________________ Sara Melo Dias vii viii Abstract Chromosomal rearrangements have been associated with multiple congenital abnormalities, including malformative syndromes and global developmental delay. The aim of this study was identification of candidate genes for a complex phenotype characterized by cardiopathy and autism, identified in an individual with a chromosome translocation t(4;7)(q21.1;p21.2). Since classical and molecular cytogenetic analyses have low resolutions, large-insert whole-genome sequencing (liWGS) was applied for identification and mapping of structural chromosomal alterations. By this approach, the 4q21.1 breakpoint was identified between genomic positions chr4:73,918,924- 74,049,529 on 4q13.3, whereas the 7p21.2 breakpoint between chr7:13,184,731-14,536,001 [GRCh38/hg38]; suggesting the occurrence of deletions at both breakpoints. Additionally, a 473Kb deletion on 2p16.3 was also identified in the proband. Nucleotide-level resolution of the breakpoints and familial segregation analysis were carried out by amplification of the junction fragments and Sanger sequencing. At the 4q13.3 breakpoint, the 130Kb deletion erases four genes PF4, PPBP, CXCL5 and CXCL3, whereas at 7p21.2, the 1351Kb deletion removes the entire ETV1 and disrupts DGKB and the long non-coding intergenic (Linc) RNA AC011288.2. Furthermore, at this breakpoint region, genomic array analysis identified in the proband’s father a 742Kb deletion comprising DGKB and ETV but not the LincRNA AC011288.2. The maternally inherited 473Kb deletion on 2p16.3 removes the first 5 exons of NRXN1, a gene associated with Pitt-Hopkins like syndrome (OMIM #614325), susceptibility to schizophrenia and chromosome 2p16.3 deletion (OMIM #614332). Similar deletions have been reported with incomplete penetrance and variable expressivity. Several genes from the 7p21.2 breakpoint region and especially those affected by the deletion, DGKB, ETV1 and LincRNA AC011288.2, have been linked with cognitive, speech, language and auditory disorders. In conclusion, coinheritance of the maternally derived deletion on 2p16.3 and the deletion at the breakpoint of the der(7) on 7p21.2 appear to be the most contributively alterations for the proband’s phenotype. At the time, NRXN1, DGKB, ETV1 and LincRNA AC011288.2 are the most likely genes to be responsible for the proband’s phenotype, being those mainly characterised by cardiopathy and autism. Keywords: Cardiopathy, Autism, Chromosomal Rearrangement, NRXN1, DGKB, ETV1 ix x Resumo Os rearranjos cromossómicos estruturais têm sido associados a anomalias congénitas incluindo síndromes malformativas e atraso global do desenvolvimento. O objetivo deste estudo foi identificar os genes candidatos para um fenótipo caracterizado por cardiopatia e autismo, presente num individuo com o rearranjo cromossómico t(4;7)(q21.1;p21.2). Visto que as análises de citogenética clássica e molecular têm baixa resolução, a sequenciação pangenómica de grandes insertos foi a metodologia usada para mapear as alterações cromossómicas estruturais. Através desta abordagem determinou- se que o ponto de quebra previamente identificado em 4q21.1, está na região chr4:73.918.924- 74.049.529 em 4q13.3, e que o ponto de quebra de 7p21.2 está na região chr7:13.184.731-14.536.001, [GRCh38/hg38] sugerindo a ocorrência de deleções nos pontos de quebra. Adicionalmente, foi identificada uma deleção de 473Kb em 2p16.3 no probando. A determinação dos pontos de quebra com resolução nucleotídica e os estudos de segregação familiar foram feitos por amplificação e sequenciação Sanger dos fragmentos de junção. No ponto de quebra em 4q13.3 a deleção de 130Kb elimina 4 genes, PF4, PPBP, CXCL5 e CXCL3, enquanto que em 7p21.2 a deleção de 1351Kb remove ETV1 e interrompe DGKB e o LincRNA AC011288.2. em 7.21.2 o array genómico identificou uma deleção de 742Kb no pai do probando, envolvendo apenas DGKB e ETV1. A deleção de 473Kb, de origem materna, elimina os 5 exões iniciais de NRXN1, um gene associado a síndrome de Pitt-Hopkins (OMIM #614325), suscetibilidade para esquizofrenia e a deleções em 2p16.3 (OMIM #614332). Deleções semelhantes foram reportadas como tendo penetrância incompleta e expressividade variável. Vários genes em 7p21.1 têm sido associados a desordens cognitivas, de linguagem e auditivas. Em suma, A co-herança da deleção materna em 2p16.3 e a deleção associada ao ponto de quebra do der(7) em 7p21.2, aparentam ser as alterações cromossómicas com maior contribuição para o fenótipo. Assim, NRXN1, DGKB, ETV1 e LincRNA AC011288.2 foram identificados como sendo os genes mais prováveis de serem causadores do fenótipo de cardiopatia e autismo apresentado pelo probando. Palavras chave: Cardiopatia, Autismo, Rearranjo Cromossómico, NRXN1, DGKB, ETV1 xi xii Table of Contents Acknowlegments ...................................................................................................................................
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