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Daniel Lopo Polla.Pdf Pró-Reitoria de Pós-Graduação e Pesquisa Programa de Pós-Graduação Stricto Sensu em Ciências Genômicas e Biotecnologia SEQUENCIAMENTO DE EXOMA PARCIAL COMO FERRAMENTA DE DIAGNÓSTICO MOLECULAR DE DISPLASIAS ESQUELÉTICAS Autor: Daniel Lôpo Polla Orientador: Dr. Robert Pogue Coorientador: Dr. Rinaldo Wellerson Pereira Brasília - DF 2014 DANIEL LÔPO POLLA SEQUENCIAMENTO DE EXOMA PARCIAL COMO FERRAMENTA DE DIAGNÓSTICO MOLECULAR DE DISPLASIAS ESQUELÉTICAS Dissertação apresentada ao Programa de Pós-graduação Stricto Sensu em Ciências Genômicas e Biotecnologia da Universidade Católica de Brasília, como requisito parcial para a obtenção do Título de Mestre em Ciências Genômicas e Biotecnologia. Orientador: Dr. Robert Pogue Coorientador: Dr. Rinaldo Wellerson Pereira Brasília 2014 P771s Polla, Daniel Lôpo. Sequenciamento de exoma parcial como ferramenta de diagnóstico molecular de displasias esqueléticas. / Daniel Lôpo Polla – 2014. 133 f.; il : 30 cm Dissertação (mestrado) – Universidade Católica de Brasília, 2014. Orientação: Prof. Dr. Robert Pogue Coorientação: Prof. Dr. Rinaldo Wellerson Pereira 1. Biotecnologia. 2. Diagnóstico molecular. 3. Displasia esquelética. I. Pogue, Robert, orient. II. Pereira, Rinaldo Wllerson, coorient. III. Título. CDU 577.21 Ficha elaborada pela Biblioteca Pós-Graduação da UCB Dissertação de autoria de Daniel Lôpo Polla, intitulada “SEQUENCIAMENTO DE EXOMA PARCIAL COMO FERRAMENTA DE DIAGNÓSTICO MOLECULAR DE DISPLASIAS ESQUELÉTICAS”, apresentada como requisito parcial para a obtenção de grau de Mestre em Ciências Genômicas e Biotecnologia da Universidade Católica de Brasília, em 12 de março de 2014, defendida e aprovada pela banca examinadora abaixo assinada: Brasília 2014 AGRADECIMENTOS Agradeço em primeiro lugar a Deus que iluminou o meu caminho durante mais esta caminhada, dando-me força e paciência para superar os desafios. Aos meus pais, Airton Polla e Marley de Sousa Lôpo Polla, e irmã Rafaela, que me apoiaram, deram forças, me ajudaram a trilhar o meu caminho e confiaram no meu potencial. À minha tia e madrinha Marly de Sousa Lôpo, pois a realização de mais essa etapa da minha vida não seria possível sem o seu incentivo, afeto e confiança. A toda minha família, que direta ou indiretamente, me deram forças e me apoiaram a concluir mais uma etapa dessa carreira que eu amo. Aos professores que me deram força para chegar até aqui, em especial à Prof. Dra. Cristine C Barreto, que me apresentou à pesquisa científica e influenciou diretamente a minha escolha para seguir essa carreira, à Prof. Dra. Juliana Mazzeu, que abriu portas para a continuidade da minha carreira científica com a minha indicação para o doutorado nos Países Baixos, e ao Prof. Dr. Robert Pogue, por todos os ensinamentos, paciência e por ter acreditado em mim e no meu trabalho, sendo peça fundamental para a concretização dessa etapa acadêmica. À Camila Fernandes, da FCAV-UNESP de Jaboticabal-SP, por ter me auxiliado durante uma etapa crucial do meu trabalho e me ajudou na fragmentação das minhas amostras. À Dra. Alessandra Reis e ao Adevilton, pela ajuda durante o sequenciamento no MiSeq. Às Dras. Cristina e Rose, por toda a ajuda nas reuniões para análise dos dados e diagnóstico dos pacientes. Aos amigos e colegas da UCB (principalmente Lana, Ohana, Tainá, Débora, Daiva e Michelle) que sempre me incentivaram e se prontificaram a me ajudar, além de todos os momentos de desconcentração. Agradeço também a todos do grupo de pesquisa do Prof. Robert, especialmente à Isabela, pela ajuda no sequenciamento das mutações na população e à Mayara que me incentivou e me ajudou sempre que precisei principalmente nas confirmações das mutações nos pacientes por sequenciamento de Sanger e toda a ajuda durante a análise dos dados. A todos que me ajudaram direta ou indiretamente para o desenvolvimento deste projeto, meu muito obrigado. RESUMO POLLA, Daniel Lôpo. Sequenciamento de exoma parcial como ferramenta de diagnóstico molecular de displasias esqueléticas. 2014. 133p. Dissertação (Mestrado em Ciências Genômicas e Biotecnologia) - Universidade Católica de Brasília, Brasília, 2014. As displasias esqueléticas compreendem um grande grupo de mais de 450 doenças clinicamente distintas e geneticamente heterogêneas associadas a mutações em mais de 300 genes. Avaliações clínicas e achados radiológicos são utilizados para o diagnóstico dessas doenças. No entanto, devido à heterogeneidade genética dos fenótipos, seu diagnóstico definitivo é complexo. Com o desenvolvimento de técnicas moleculares e a elucidação das bases moleculares dessas doenças, os testes moleculares se tornaram úteis no auxílio do diagnóstico dessas displasias. Uma vez que diversos genes têm sido associados a estas doenças, abordagens padrão para seu diagnóstico molecular, utilizando o sequenciamento de Sanger, podem ser demoradas e ter um alto custo. Para superar essas limitações, foi utilizado o sequenciamento de exoma parcial e construído um painel de 1,4Mb para a captura de todos os éxons de 309 genes envolvidos em displasias esqueléticas, além de 28 regiões genômicas que sofrem deleções associadas com essas doenças. O objetivo principal foi o de fornecer uma ferramenta que possa analisar simultaneamente e com alta confiança todos os genes conhecidos relacionados às displasias esqueléticas, produzindo dados que possam ser cruzados com informações clínicas para chegar a um diagnóstico definitivo. Amostras de DNA de 93 indivíduos, com diagnóstico clínico prévio de displasia esquelética, foram sequenciados multiplexados em oito corridas usando a plataforma de sequenciamento de DNA Illumina® MiSeq®. A reprodutibilidade da metodologia foi testada repetindo todo o processo em três amostras. O sequenciamento de alto desempenho dos éxons capturados resultou em uma cobertura média de 140X. Mutações causais foram caracterizadas em 15 pacientes até o momento, incluindo 7 mutações não reportadas anteriormente. A confirmação de 9 mutações foi realizada por meio do sequenciamento de Sanger e todas foram confirmadas. O painel de genes construído nesse trabalho fornece uma ferramenta de diagnóstico molecular rápida, precisa e de baixo custo e pode auxiliar no diagnóstico definitivo de doenças esqueléticas. Palavras-chave: Diagnóstico molecular. Displasias Esqueléticas. Sequenciamento NGS. Exoma parcial. ABSTRACT POLLA, Daniel Lôpo. Targeted exome sequencing as a molecular diagnostic tool for skeletal dysplasias. 2014. 133p. Dissertation for a diploma (Master’s Degree in Genomic Sciences and Biotechnology) – Catholic University of Brasília, Brasília, Brazil, 2014. Skeletal dysplasias comprise a large group of more than 450 clinically distinct and genetically heterogeneous diseases associated with mutations in more than 300 genes. Clinical and radiological findings are used to diagnose these diseases. However, due to the genetic heterogeneity of these disorders, the diagnostic process is complex. With advances in molecular genetics and the elucidation of the molecular basis of many of these diseases, molecular tests have become useful in the diagnosis of skeletal dysplasias. Since many different genes have been associated with these disorders, standard diagnostic approaches using Sanger sequencing can be expensive and time consuming. To overcome these limitations, we used targeted exome sequencing and designed a 1.4Mb panel for simultaneous testing of more than 4800 exons in 309 genes involved in skeletal dysplasias, as well as 28 genomic regions which when deleted are associated with these diseases. The main objective was to provide a tool which can analyze all of the known skeletal dysplasia genes simultaneously with high confidence, producing data which can be crossed with clinical information to reach a definitive diagnosis. DNA samples from 93 individuals with previous clinical diagnosis of skeletal dysplasia were sequenced in 8 multiplexed runs using an Illumina MiSeq sequencer. Reproducibility was tested by repeating the entire procedure for three samples. NGS of the captured exons resulted in an average coverage of 140X. Causative mutations were characterized in 15 patients so far including previously unreported mutations in 7 cases. Analysis of the rest of the data is ongoing. Confirmation with Sanger sequencing was performed for 9 variants and all were confirmed. This NGS panel provides a fast, accurate and cost-effective molecular diagnostic tool and can assist in the diagnosis of skeletal diseases. Keywords: Molecular diagnosis. Skeletal dysplasias. NGS. Targeted Sequencing. Exome. LISTA DE ABREVIATURAS µ micro (10-6) CCD Charge-coupled device CDS Coding DNA Sequence CNV Copy Number Variation dbNSFP Database for nonsynonymous SNPs' functional predictions dbSNP Single Nucleotide Polimorphism Database ddNTP Didesoxinucleotídeo dNTP Desoxinucleotídeo dsDNA Double-stranded DNA FCAV Faculdade de Ciências Agrárias e Veterinárias g Gramas Gb Gigabase (109) HGMD Human Genome Mutation Database indels Inserções/deleções k Kilo Kb Kilobase (103) LOH Loss of heterozigosity m mili (10-3) M Molar (mol/L) Mb Megabase (106) n nano (10-9) NCBI National Center for Biotechnology Information NGS Next-Generation Sequencing Nugen Serviço de Genética Clínica da Secretaria de Saúde do DF OMIM Online Mendelian Inheritance in Man p Pico (10-12) pb Pares de base PCR Reação da polimerase em cadeia PF Passing filter Q Phred score qPCR PCR quantitativa ROI Regions of interest rpm Rotações por minuto SNP Single Nucleotide Polimorphism SNV Single Nucleotide Variation UCB Universidade Católica de Brasília UCSC University
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