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Exome sequencing and targeted gene panels: a simulated comparison of diagnostic yield using data from 158 patients with rare diseases

2021; Brazilian Society of Genetics; Volume: 44; Issue: 4 Linguagem: Inglês

10.1590/1678-4685-gmb-2021-0061

1678-4685

Caio Robledo D’Angioli Costa Quaio, María José Rivadeneira Obando, Sandro Félix Perazzio, Aurélio Pimenta Dutra, Christine Hsiaoyun Chung, Caroline Mônaco Moreira, Gil Monteiro Novo Filho, Patricia Rossi Sacramento‐Bobotis, Michele Groenner Penna, Rafaela Rogerio Floriano de Souza, Vívian Pedigone Cintra, Juliana Emilia Prior Carnavalli, Rafael Alves da Silva, Monize Nakamoto Provisor Santos, Daniele Paixão, Wagner Antonio da Rosa Baratela, Caroline Olivati, Gustavo Marquezani Spolador, Maria Carolina Tostes Pintão, Alexandre Ricardo dos Santos Fornari, Matheus Carvalho Bürger, Rodrigo Fernandes Ramalho, Otavio Jose Eulalio Pereira, Elisa Napolitano Ferreira, Miguel Mitne‐Neto, Chong Ae Kim,

Genomic variations and chromosomal abnormalities

Next-generation sequencing (NGS) has altered clinical genetic testing by widening the access to molecular diagnosis of genetically determined rare diseases. However, physicians may face difficulties selecting the best diagnostic approach. Our goal is to estimate the rate of possible molecular diagnoses missed by different targeted gene panels using data from a cohort of patients with rare genetic diseases diagnosed with exome sequencing (ES). For this purpose, we simulated a comparison between different targeted gene panels and ES: the list of genes harboring clinically relevant variants from 158 patients was used to estimate the theoretical rate of diagnoses missed by NGS panels from 53 different NGS panels from eight different laboratories. Panels presented a mean rate of missed diagnoses of 64% (range 14%-100%) compared to ES, representing an average predicted sensitivity of 36%. Metabolic abnormalities represented the group with highest mean of missed diagnoses (86%), while seizure represented the group with lowest mean (46%). Focused gene panels are restricted in covering select sets of genes implicated in specific diseases and they may miss molecular diagnoses of rare diseases compared to ES. However, their role in genetic diagnosis remains important especially for well-known genetic diseases with established genetic locus heterogeneity.