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Universidade Estadual De Campinas Faculdade De 1 UNIVERSIDADE ESTADUAL DE CAMPINAS FACULDADE DE CIÊNCIAS MÉDICAS ILÁRIA CRISTINA SGARDIOLI Investigação da Síndrome de deleção 22q11.2 utilizando diferentes estratégias para aplicação em saúde CAMPINAS 2018 ii Ilária Cristina Sgardioli Investigação da Síndrome de deleção 22q11.2 utilizando diferentes estratégias para aplicação em saúde Tese apresentada à Faculdade de Ciências Médicas da Universidade Estadual de Campinas como parte dos requisitos exigidos para a obtenção do título de Doutora em Ciências, Área de Concentração Genética Médica. Orientadora: Profa. Dra. Vera Lúcia Gil da Silva Lopes Coorientador: Prof. Dr. Társis Antonio Paiva Vieira Este exemplar corresponde a versão final da Tese defendida pela aluna Ilária Cristina Sgardioli, orientada pela Profa. Dra. Vera Lúcia Gil-da-Silva Lopes. CAMPINAS 2018 iii Agência(s) de fomento e nº(s) de processo(s): Não se aplica. ORCID: https://orcid.org/0000-0002-7253-7830 Ficha catalográfica Universidade Estadual de Campinas Biblioteca da Faculdade de Ciências Médicas Maristella Soares dos Santos – CRB 8/8402 Sgardioli, Ilária Cristina, 1981- Sg16i Investigação da síndrome de deleção 22q11.2 utilizando diferentes estratégias para aplicação em saúde / Ilária Cristina Sgardioli. – Campinas, SP : [s.n.], 2018. Orientador: Vera Lúcia Gil da Silva Lopes. Coorientador: Társis Antonio Paiva Vieira. Tese (doutorado) – Universidade Estadual de Campinas, Faculdade de Ciências Médicas. 1. Síndrome da deleção 22q11.2. 2. Hibridização genômica comparativa. 3. Variações do número de cópias de DNA. 4. Perda de heterozigosidade. I. Lopes, Vera Lúcia Gil da Silva, 1967-. II. Vieira, Társis Antonio Paiva, 1981-. III. Universidade Estadual de Campinas. Faculdade de Ciências Médicas. IV. Título. Informações para Biblioteca Digital Título em outro idioma: Investigation of 22q11.2 deletion syndrome using different strategies for an approach focused on healthcare Palavras-chave em inglês: 22q11.2 deletion syndrome Comparative genomic hybridization DNA copy number variations Loss of heterozygosity Área de concentração: Genética Médica Titulação: Doutora em Ciências Banca examinadora: Vera Lúcia Gil da Silva Lopes [Orientador] Maria Isabel de Souza Aranha Melaragno Vera de Freitas Ayres Meloni Cláudia Vianna Maurer Morelli Carmem Silvia Bertuzzo Data de defesa: 27-07-2018 Programa de Pós-Graduação: Ciências Médica iv BANCA EXAMINADORA DA DEFESA DE DOUTORADO ILÁRIA CRISTINA SGARDIOLI ORIENTADOR: Vera Lúcia Gil-da-Silva-Lopes COORIENTADOR: Társis Antonio Paiva Vieira MEMBROS: 1. PROFA. DRA. VERA LÚCIA GIL-DA-SILVA-LOPES 2. PROFA. DRA. MARIA ISABEL DE SOUZA ARANHA MELARAGNO 3. PROFA. DRA. VERA DE FREITAS AYRES MELONI 4. PROFA. DRA. CLÁUDIA VIANNA MAURER MORELLI 5. PROFA. DRA. CARMEM SILVIA BERTUZZO Programa de Pós-Graduação em Ciências Médicas da Faculdade de Ciências Médicas da Universidade Estadual de Campinas. A ata de defesa com as respectivas assinaturas dos membros da banca examinadora encontra-se no processo de vida acadêmica do aluno. Data: 27/07/2018 v Dedico este trabalho aos meus pais Manoel e Gilda, ao meu irmão Rafael e a minha avó Arlete por todo amor, dedicação e apoio em todos os momentos de minha vida. Eu os amos incondicionalmente. vi Agradecimentos Ao Universo, que me presenteia com coisas maravilhosas em minha vida, me ensinando que tudo é perfeitamente harmônico, o que nos propicia a colheita de tudo que plantamos; Aos meus pais Manoel e Gilda, que me ensinaram desde cedo que todas as coisas são possíveis, desde que desejemos de coração e nos esforcemos para isso. Muito obrigada por todo amor, carinho, compreensão e apoio; Ao meu irmão Rafael, que com sabedoria me incentiva e me apoia em momentos de maior fragilidade; À minha avó Arlete, pelo amor incondicional e pelo apoio em todos os momentos; À minha orientadora, Profa. Dra. Vera Lúcia Gil da Silva Lopes, pela oportunidade e aprendizado durante estes anos; Ao meu coorientador, Prof. Dr. Társis Antonio Paiva Vieira, pela oportunidade e por compartilhar seus conhecimentos comigo. Além disso, quero agradecer por toda sua amizade e contribuição neste trabalho, que foi imensa e de suma importância; À Banca Examinadora pela contribuição na participação e elaboração desta tese; À toda a equipe do Projeto Crânio Face Brasil, e aos pacientes e seus familiares que aceitaram participar deste estudo, tornando-o possível; vii Ao Comitê da Associação Europeia de Citogenética, pela bolsa de estudos concedida para a participação e apresentação deste trabalho na 11ª Conferência Europeia de Citogenética em Florença, de 1 a 4 de julho de 2017; À Marcinha, secretária do curso de Pós-Graduação em Ciências Médicas, pela paciência e disponibilidade de sempre; Aos funcionários e ex-funcionários do Laboratório de Citogenética Humana e Laboratório de Genética Humana Molecular, bem como aos alunos e ex-alunos pertencentes aos mesmos; pelas diversas técnicas laboratoriais realizadas e pela companhia destes anos. viii RESUMO A Síndrome de Deleção 22q11.2 (SD22q11.2 – OMIM: #188400 e #192430) tem incidência estimada de 1/4.000 a 1/6.000 nascimentos. A heterogeneidade clínica desta afecção é um desafio universal para a sua suspeita. No Brasil o diagnóstico se dá por volta de 10 anos de idade, comprometendo o manejo apropriado e o aconselhamento genético. O objetivo deste trabalho foi avaliar possíveis estratégias para o diagnóstico de indivíduos com suspeita clínica de SD22q11.2, considerando duas propostas anteriores do Projeto Crânio-Face Brasil: aplicação de critérios clínicos específicos para a investigação laboratorial da SD22q11.2 e utilização de uma aplicação on-line para registro, seguimento e somatória desses critérios, a “CranFlow: craniofacial anomalies registration, flow and management”. Foram revisados os dados clínicos e laboratoriais de 347 indivíduos registrados na Base Brasileira de Anomalias Craniofaciais /Síndrome de Deleção 22q11.2, no período de 2008 a 2017, inicialmente investigados para a SD22q11.2 por Hibridação in situ com Fluorescência (FISH) e/ou Amplificação de múltiplas sondas dependente de ligação (MLPA), detectando ao todo 98 casos positivos para a SD22q11.2 e cinco deleções atípicas em 22q11.2. Os 347 indivíduos foram divididos em dois grupos: (I) 168 indivíduos investigados antes da aplicação dos critérios e (II) 179 indivíduos investigados após aplicação dos critérios. A detecção da SD22q11.2 no Grupo I e no Grupo II foi de 26,79% e 29,61%, respectivamente. No Grupo II, a presença de indivíduos com SD22q11.2 e de critérios preenchidos (42,42%) foi significante quando comparada aos 13,75% que não preencheram os critérios e apresentam deleção em 22q11.2. Foi significantemente relacionada à presença da SD 22q11.2, a associação de cardiopatias congênitas de alto valor preditivo e voz anasalada. Portanto, a análise da aplicação dos critérios clínicos propostos se mostrou uma ferramenta útil para a suspeita diagnóstica, uma vez que permitiu um incremento diagnóstico de 3,82 vezes. Dos 249 casos negativos para SD22q11.2, a análise cromossômica em microarranjos (CMA) foi realizada para 133, cujos resultados foram ix reanalisados neste estudo com parâmetros atualizados de interpretação. Em 34 indivíduos os resultados foram diferentes dos anteriores, possibilitando duas conclusões diagnósticas adicionais, além de sugerir a investigação complementar de três casos com suspeita de dissomia uniparental (UDP). As diferentes abordagens utilizadas neste estudo permitiram a conclusão diagnóstica de 117 casos (33,7%) da amostra, reforçando a complexidade da investigação genético-clínica. Embora, de modo geral, a CMA apresente maior rendimento diagnóstico, a aplicação dos critérios clínicos pode favorecer o diagnóstico quando utilizado em conjunto com técnicas locus-específicas, em situações em que a utilização de CMA não seja possível em larga escala. Ainda, na ausência de SD22q11.2, a investigação por CMA utilizando os parâmetros aplicados neste estudo impactariam positivamente no número de casos com diagnóstico conclusivo. Considerando uma possível estratégia para investigação da SD22q11.2 em larga escala, pode-se sugerir: a) treinamento de equipes; b) utilização dos critérios clínicos propostos e da CranFlow para registro e seguimento dos casos com suspeita desta microdeleção; c) hierarquização de exames genéticos, e d) centralização da investigação laboratorial pública. A proposta apresentada tem relevância universal e é aplicável ao Sistema Único de Saúde. Palavras-chave: Síndrome de Deleção 22q11.2, Hibridação in situ com Fluorescência, Amplificação de Múltiplas Sondas Dependente de Ligação, Análise Cromossômica em Microarranjos, Variação no Número de Cópias, Perda de Heterozigose. x ABSTRACT The 22q11.2 Deletion Syndrome (22q11.2DS - OMIM: # 188400 and # 192430) has an estimated incidence of 1/4,000 to 1/6,000 births. The clinical heterogeneity of this condition is a universal challenge for its suspicion. In Brazil, the diagnosis occurs around 10 years of age, compromising appropriate management and genetic counseling. The aim of this study was to evaluate possible strategies for the diagnosis of individuals with clinical suspicion of 22q11.2DS, considering two previous proposals from Brazil´s CranioFacial Project: application of specific clinical criteria to proceed laboratory investigation of 22q11.2DS and use of an on- line application for registration, follow-up and summation of these criteria, the "CranFlow: craniofacial anomalies registration, flow and management". We reviewed the clinical and laboratory data of 347 individuals
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