Análise da patogenicidade de variantes de significado incerto detectadas no sequenciamento de genoma em uma clínica de genética em Curitiba/PR
Tipo
TCC
Data de publicação
2025-06-26
Periódico
Citações (Scopus)
Autores
Schroeder, Ana Júlia
Souza, Júlia Jussim
Souza, Júlia Jussim
Orientador
Wormsbecker, Liya Regina Mikami
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Introdução: O genoma humano possui cerca de 3 bilhões de nucleotídeos organizados em 23 pares de cromossomos e aproximadamente 20 mil genes. Embora 99% da sequência seja comum, variações podem influenciar o risco de doenças e a resposta a tratamentos. O sequenciamento genômico (GWS) permite identificar variantes patogênicas ou de significado clínico incerto (VUS). A interpretação das VUS é complexa, pois muitas não possuem dados suficientes sobre sua função ou associação com doenças, sendo que sua classificação é dinâmica, podendo mudar com novos estudos. A compreensão dessas variantes é essencial para diagnósticos precisos, terapias personalizadas e melhor prognóstico. Objetivos: Este estudo tem como objetivo correlacionar variantes de significado incerto (VUS) identificadas em pacientes de um laboratório de genética em Curitiba com seu potencial patogênico, além de estimar a frequência das VUS, avaliar variantes patogênicas, identificar as principais queixas clínicas associadas e analisar variantes inéditas na literatura científica. Metodologia: Foi realizada uma análise retrospectiva de 86 prontuários de pacientes que realizaram o sequenciamento de genoma em uma clínica de genética de Curitiba, Paraná de 2018 a 2024. Resultados: Os prontuários analisados dos pacientes submetidos ao sequenciamento completo do genoma, com predominância de homens (57%) e média de idade de 12,5 anos, sendo 72,1% menores de 18 anos. As principais condições clínicas incluíram alterações neurológicas (65,1%). Diagnóstico genético foi confirmado em 36% dos casos. Variantes foram identificadas em 79,1% dos pacientes, sendo que a maioria das foi de significado incerto (39,7%), seguida de patogênicas e provavelmente patogênicas. Sites de predições in silico indicaram que algumas variantes são potencialmente prejudiciais, existindo, portanto, possibilidade de reclassificação dessa variante. Conclusão: A correlação genótipo-fenótipo identificou que 4 das 29 VUS analisadas possuem forte associação clínica, sugerindo provável potencial de reclassificação como patogênicas, auxiliando no esclarecimento do papel funcional dessas variantes.
Introduction: The human genome contains approximately 3 billion nucleotides organized into 23 pairs of chromosomes and about 20,000 genes. Although 99% of the sequence is shared among individuals, variations can influence disease risk and response to treatment. Genomic sequencing (GWS) enables the identification of pathogenic variants or variants of uncertain significance (VUS). Interpreting VUS is complex, as many lack sufficient data regarding their function or disease association. Their classification is dynamic and may change as new research emerges. Understanding these variants is essential for accurate diagnoses, personalized therapies, and improved prognosis. Objectives: This study aims to correlate variants of uncertain significance (VUS) identified in patients from a genetics laboratory in Curitiba with their pathogenic potential. It also seeks to estimate the frequency of VUS, assess pathogenic variants, identify the main associated clinical complaints, and analyze novel variants not previously reported in the scientific literature. Methodology: A retrospective analysis was conducted on 86 medical records of patients who underwent genome sequencing at a genetics clinic in Curitiba, Paraná, between 2018 and 2024. Results: The analyzed records included patients who underwent whole genome sequencing, with a predominance of males (57%) and an average age of 12.5 years; 72.1% were under 18 years old. The main clinical conditions included neurological alterations (65.1%). A genetic diagnosis was confirmed in 36% of cases. Variants were identified in 79.1% of patients, with the majority being of uncertain significance (39.7%), followed by pathogenic and likely pathogenic variants. In silico prediction tools indicated that some variants are potentially deleterious, suggesting the possibility of variant reclassification. Conclusion: Genotype-phenotype correlation revealed that 4 out of the 29 analyzed VUS showed strong clinical associations, suggesting a probable potential for reclassification as pathogenic. This contributes to a better understanding of the functional role of these variants.
Introduction: The human genome contains approximately 3 billion nucleotides organized into 23 pairs of chromosomes and about 20,000 genes. Although 99% of the sequence is shared among individuals, variations can influence disease risk and response to treatment. Genomic sequencing (GWS) enables the identification of pathogenic variants or variants of uncertain significance (VUS). Interpreting VUS is complex, as many lack sufficient data regarding their function or disease association. Their classification is dynamic and may change as new research emerges. Understanding these variants is essential for accurate diagnoses, personalized therapies, and improved prognosis. Objectives: This study aims to correlate variants of uncertain significance (VUS) identified in patients from a genetics laboratory in Curitiba with their pathogenic potential. It also seeks to estimate the frequency of VUS, assess pathogenic variants, identify the main associated clinical complaints, and analyze novel variants not previously reported in the scientific literature. Methodology: A retrospective analysis was conducted on 86 medical records of patients who underwent genome sequencing at a genetics clinic in Curitiba, Paraná, between 2018 and 2024. Results: The analyzed records included patients who underwent whole genome sequencing, with a predominance of males (57%) and an average age of 12.5 years; 72.1% were under 18 years old. The main clinical conditions included neurological alterations (65.1%). A genetic diagnosis was confirmed in 36% of cases. Variants were identified in 79.1% of patients, with the majority being of uncertain significance (39.7%), followed by pathogenic and likely pathogenic variants. In silico prediction tools indicated that some variants are potentially deleterious, suggesting the possibility of variant reclassification. Conclusion: Genotype-phenotype correlation revealed that 4 out of the 29 analyzed VUS showed strong clinical associations, suggesting a probable potential for reclassification as pathogenic. This contributes to a better understanding of the functional role of these variants.
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Palavras-chave
genoma , variantes de significado incerto , patogenicidade , genome , variants of uncertain significance , pathogenicity