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Universidade Presbiteriana Mackenzie Centro De Cienciâs Biológicas E Da Saúde Curso De Ciências Biológicas

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Universidade Presbiteriana Mackenzie Centro De Cienciâs Biológicas E Da Saúde Curso De Ciências Biológicas UNIVERSIDADE PRESBITERIANA MACKENZIE CENTRO DE CIENCIÂS BIOLÓGICAS E DA SAÚDE CURSO DE CIÊNCIAS BIOLÓGICAS Ariane Miranda de Freitas Juliana Lopes Mussolini Transtorno do Espectro Autista: estudo de uma série de casos com alterações genéticas São Paulo 2016 UNIVERSIDADE PRESBITERIANA MACKENZIE CENTRO DE CIÊNCIAS BIOLÓGICAS E DA SAÚDE CURSO DE CIÊNCIAS BIOLÓGICAS Ariane Miranda de Freitas Juliana Lopes Mussolini Transtorno do Espectro Autista: estudo de uma série de casos com alterações genéticas Monografia apresentada ao Centro de Ciências Biológicas e da Saúde, da Universidade Presbiteriana Mackenzie como parte dos requisitos exigidos para a conclusão do Curso de Bacharelado em Ciências Biológicas. Área: Citogenética Humana Orientador: Prof.º Dr.º Decio Brunoni São Paulo 2016 “ No fim do dia não sonhamos nossas vidas...nós vivemos elas! ” Anthony Ianni Agradecimentos Agradecemos, primeiramente, à Universidade Presbiteriana Mackenzie por nos proporcionar um excelente curso, com professores excepcionais e atenciosos, que nos guiaram, inspiraram e proporcionaram uma visão mais humana e ética da Biologia. Ao nosso orientador Prof.° Dr. Decio Brunoni, que nos orientou e ensinou tanto nesse último ano, crucial para nossas vidas acadêmicas e profissionais. Um agradecimento especial ao coordenador do curso, Prof.° Dr. Adriano Monteiro de Castro, pelo apoio, carinho, atenção e conselhos quando decidimos enfrentar essa última etapa do curso juntas. Agradecemos imensamente aos nossos queridos pais, Andréa e Juliano, Adriana e Paulo, por todo o carinho, suporte, paciência e, acima de tudo, amor por nós. Aos demais familiares, um muito obrigada, por nos acompanhar por toda essa trajetória, pelos abraços, risadas, lágrimas e, agora, estarem presentes em mais uma vitória em nossas vidas. Um obrigada muito especial para os nossos namorados, José Valério e Danilo, pelo apoio, pela paciência, compreensão e estarem sempre ao nosso lado, independente do que houver nos nossos caminhos. Um grande agradecimento à UNIFESP e à Dra. Thais Zanolla por nos receber e conceder conhecimentos imprescindíveis ao nosso trabalho. À Dra. Leslie Kulikowski e toda a sua equipe por nos receber, ensinar e inspirar do começo ao fim nessa difícil trajetória que foi esse último ano. Resumo O Transtorno do Espectro Autista (TEA) é um distúrbio do neurodesenvolvimento com acometimento na comunicação e interação social, além de comportamentos e atividades restritos e repetitivos. Afetando cerca de 1% da população o TEA possui um quadro clínico heterogêneo, além de diversas síndromes e psicopatias em comorbidade. Entre os fatores causais sabe-se que as causas genéticas representam até 20% sendo que as copy number variations (CNVs) na forma de microdeleções e microduplicações são as principais. Estas alterações citogenômicas envolvem dezenas de genes. O objetivo do presente trabalho é o descrever uma amostra de conveniência das alterações genéticas encontradas em 6 pacientes com TEA. Os pacientes foram averiguados na Clínica TEA da Universidade Presbiteriana Mackenzie e os testes genéticos foram realizados em laboratórios comerciais. Cinco pacientes foram diagnosticados pelo array genômico e um pelo sequenciamento do exoma. A interpretação das coordenadas genômicas foi realizada com ferramentas de bioinformática usuais como o genome browser. As regiões cromossômicas envolvidas foram: 3p26.3; 6q; 7q31.3; 7q36.3; 9p21.1; 17q22 e os possíveis genes relevantes na manifestação do quadro clínico são: B4GALT1, PTPRN2, CNTN4, CNTN6, OXTR, GRM7, SETD5, BZRAP1, SYNGAP1 e IMMP2L. Estes resultados já foram publicados em outros pacientes com TEA. Centenas de amostras de pacientes com TEA são relatadas na literatura internacional. Os indivíduos que apresentam alterações genéticas similares aos dos pacientes aqui estudados tem em comum a deficiência intelectual. Assim essa característica clinica deve ser a principal indicação para investigar uma comorbidade de causa genética em pacientes com TEA. Palavras-Chave: Autismo, TEA, CNVs, aCGH-Array, alterações genéticas, genes candidatos. Abstract The Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with communication and social interaction impairments, also repetitive and restricted behaviors. Affecting about 1% of population, ASD has a heterogeneous clinical picture, besides several syndromes and psychopathies in comorbidity. Between the causal factors, it’s known that the genetic causes represent up to 20% being that the copy number variations (CNVs) in microdeletions and microduplications forms are the principal ones. These citogenomic alterations involve dozens of genes. The objective of this present work is to describe a convenience sample found in 6 ASD patients. The patients were investigated in the Clínicas TEA of Universidade Presbiteriana Mackenzie and the testes were performed in comercial laboratories. Five patients were diagnosed by MicroArray and one by exoma sequencing. The genomic coordinates interpretation was performed with usual bioinformatics tools, like Genome Browser. The cromossomic regions involved were: 3p26.3; 6q; 7q31.3; 7q36.3; 9p21.1; 17q22 and the possible relevant genes in the manifestation of the clinical picture were: B4GALT1, PTPRN2, CNTN4, CNTN6, OXTR, GRM7, SETD5, BZRAP1, SYNGAP1 e IMMP2L. These results were already been published in other patients with ASD. Hundreds of ASD patients samples are mentioned in international literature. Individuals who present genetic alterations similar to the studied patients has in common the intelectual desability. Thus, this clinical feature should be the main indication to investigate a genetic cause comorbidity in patients with ASD. Key-Words: Autism, ASD, CNVs, MicroArray, genetic alterations, candidate genes. Índice QUADRO 1. CARACTERIZAÇÃO DO TEA SEGUNDO O DSM-V. ............................................... 10 QUADRO 2. AUTISMO SINDRÔMICO COM CNVS RECORRENTES. ............................................ 12 QUADRO 3. GENES CANDIDATOS PARA TEA. ...................................................................... 13 QUADRO 4. RESULTADOS GERAIS ...................................................................................... 18 Sumário 1. INTRODUÇÃO .................................................................................................. 8 2. REVISÃO BIBLIOGRÁFICA ............................................................................. 9 2.1. MANIFESTAÇÕES CLÍNICAS ................................................................... 9 2.2. CAUSAS GENÉTICAS ............................................................................. 11 2.3. TESTES GENÉTICOS ............................................................................. 14 3. MÉTODO E CASUÍSTICA .............................................................................. 15 3.1. CASUÍSTICA ................................................................................................... 15 3.2. MÉTODOS ..................................................................................................... 16 4. RESULTADOS ............................................................................................... 17 5. DISCUSSÃO ................................................................................................... 19 5.1. CASO 1 ...................................................................................................... 19 5.2. CASO 2 ...................................................................................................... 19 5.3. CASO 3 ...................................................................................................... 20 5.4. CASO 4 ...................................................................................................... 23 5.5. CASO 5 ...................................................................................................... 23 5.6. CASO 6 ...................................................................................................... 24 6. CONCLUSÃO ................................................................................................. 25 7. REFERÊNCIAS BIBLIOGRÁFICAS ............................................................... 26 8 1. INTRODUÇÃO Segundo o DSM-V, Manual Diagnóstico e Estatístico de Transtornos Mentais, o Transtorno do Espectro Autista é um distúrbio do neurodesenvolvimento, com déficits persistentes na comunicação e interação social e padrões restritos e repetitivos de comportamento. Com um fenótipo muito heterogêneo, os sintomas começam a se manifestar aos três anos, de tal maneira que já é possível o seu diagnóstico. Intensa pesquisa interdisciplinar, principalmente a partir dos anos de 1970, estabeleceu o TEA como um transtorno que afeta principalmente indivíduos do sexo masculino. Possui prevalência em torno de 1% da população, sem predileção com antecedentes étnicos e com ampla diversidade sintomatológica na área cognitivo comportamental. Os quadros variam de muito graves, nos quais prepondera a deficiência intelectual, até os casos clínicos cujos indivíduos têm inteligência normal e razoável capacidade adaptativa. Têm sido estabelecidas, também, diversas comorbidades com TEA, como a epilepsia, o Transtorno do Déficit de Atenção com Hiperatividades e diversas síndromes genéticas e ambientais (ABRAHMS, GESCHWIND, 2010; APA, 2002; APA, 2013; CID 10, 2000; DAGLI, MUELLER, WILLIAMS, 2015; FOMBONNE, 2009; GRABRUCKER, 2013; JESTE, GESCHWIND, 2014). Quanto as causas do TEA temos as conhecidas na forma de comorbidades com síndromes genéticas e
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