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

• Published in: Genetics and molecular biology Vol. 44; no. 4; pp. 1 - 20210061
• Main Authors: Quaio, Caio Robledo D’Angioli Costa, Obando, María José Rivadeneira, Perazzio, Sandro Felix, Dutra, Aurelio Pimenta, Chung, Christine Hsiaoyun, Moreira, Caroline Monaco, Novo Filho, Gil Monteiro, Sacramento-Bobotis, Patricia Rossi, Penna, Michele Groenner, Souza, Rafaela Rogerio Floriano de, Cintra, Vivian Pedigone, Carnavalli, Juliana Emilia Prior, Silva, Rafael Alves da, Santos, Monize Nakamoto Provisor, Paixão, Daniele, Baratela, Wagner Antonio da Rosa, Olivati, Caroline, Spolador, Gustavo Marquezani, Pintao, Maria Carolina, Fornari, Alexandre Ricardo dos Santos, Burger, Matheus, Ramalho, Rodrigo Fernandes, Pereira, Otavio Jose Eulalio, Ferreira, Elisa Napolitano e, Mitne-Neto, Miguel, Kim, Chong Ae
• Format: Journal Article
• Language: English; Portuguese
• Published: Ribeirao Preto Sociedade Brasileira de Genetica 01.01.2021; Sociedade Brasileira de Genética
• Subjects: Abnormalities; BIOCHEMISTRY & MOLECULAR BIOLOGY; Diagnosis; Diagnostic systems; diagnostic yield; Exome sequencing; Gene sequencing; Genes; Genetic disorders; Genetic screening; GENETICS & HEREDITY; Heterogeneity; Human and Medical Genetics; Next-generation sequencing; NGS panel; Panels; Patients; Physicians; Rare diseases; Seizures; targeted gene panels; Next-generation sequencing; NGS panel; targeted gene panels; diagnostic yield; Exome sequencing
• ISSN: 1415-4757; 1678-4685; 1678-4685
• DOI: 10.1590/1678-4685-GMB-2021-0061

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.