Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center

Detalhes bibliográficos
Autor(a) principal: Barbosa-Gouveia, Sofia
Data de Publicação: 2021
Outros Autores: Vázquez-Mosquera, María E., González-Vioque, Emiliano, Álvarez, José V., Chans, Roi, Laranjeira, Francisco, Martins, Esmeralda, Ferreira, Ana Cristina, Avila-Alvarez, Alejandro, Couce, María L.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.16/2839
Resumo: Next-generation sequencing (NGS) technologies have been proposed as a first-line test for the diagnosis of inborn errors of metabolism (IEM), a group of genetically heterogeneous disorders with overlapping or nonspecific phenotypes. Over a 3-year period, we prospectively analyzed 311 pediatric patients with a suspected IEM using four targeted gene panels. The rate of positive diagnosis was 61.86% for intermediary metabolism defects, 32.84% for complex molecular defects, 19% for hypoglycemic/hyperglycemic events, and 17% for mitochondrial diseases, and a conclusive molecular diagnosis was established in 2-4 weeks. Forty-one patients for whom negative results were obtained with the mitochondrial diseases panel underwent subsequent analyses using the NeuroSeq panel, which groups all genes from the individual panels together with genes associated with neurological disorders (1870 genes in total). This achieved a diagnostic rate of 32%. We next evaluated the utility of a tool, Phenomizer, for differential diagnosis, and established a correlation between phenotype and molecular findings in 39.3% of patients. Finally, we evaluated the mutational architecture of the genes analyzed by determining z-scores, loss-of-function observed/expected upper bound fraction (LOEUF), and haploinsufficiency (HI) scores. In summary, targeted gene panels for specific groups of IEMs enabled rapid and effective diagnosis, which is critical for the therapeutic management of IEM patients.
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spelling Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Centerdifferential diagnosisgenetic diagnosisinborn errors of metabolismNext-generation sequencing (NGS) technologies have been proposed as a first-line test for the diagnosis of inborn errors of metabolism (IEM), a group of genetically heterogeneous disorders with overlapping or nonspecific phenotypes. Over a 3-year period, we prospectively analyzed 311 pediatric patients with a suspected IEM using four targeted gene panels. The rate of positive diagnosis was 61.86% for intermediary metabolism defects, 32.84% for complex molecular defects, 19% for hypoglycemic/hyperglycemic events, and 17% for mitochondrial diseases, and a conclusive molecular diagnosis was established in 2-4 weeks. Forty-one patients for whom negative results were obtained with the mitochondrial diseases panel underwent subsequent analyses using the NeuroSeq panel, which groups all genes from the individual panels together with genes associated with neurological disorders (1870 genes in total). This achieved a diagnostic rate of 32%. We next evaluated the utility of a tool, Phenomizer, for differential diagnosis, and established a correlation between phenotype and molecular findings in 39.3% of patients. Finally, we evaluated the mutational architecture of the genes analyzed by determining z-scores, loss-of-function observed/expected upper bound fraction (LOEUF), and haploinsufficiency (HI) scores. In summary, targeted gene panels for specific groups of IEMs enabled rapid and effective diagnosis, which is critical for the therapeutic management of IEM patients.This study was supported with a grant from ISCIII (PI13/02177)MDPIRepositório Científico do Centro Hospitalar Universitário de Santo AntónioBarbosa-Gouveia, SofiaVázquez-Mosquera, María E.González-Vioque, EmilianoÁlvarez, José V.Chans, RoiLaranjeira, FranciscoMartins, EsmeraldaFerreira, Ana CristinaAvila-Alvarez, AlejandroCouce, María L.2023-10-24T09:16:35Z2021-082021-08-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.16/2839engBarbosa-Gouveia S, Vázquez-Mosquera ME, González-Vioque E, et al. Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center. Genes (Basel). 2021;12(8):1262. doi:10.3390/genes120812622073-442510.3390/genes12081262info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-10-26T05:19:17Zoai:repositorio.chporto.pt:10400.16/2839Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:39:38.737247Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center
title Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center
spellingShingle Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center
Barbosa-Gouveia, Sofia
differential diagnosis
genetic diagnosis
inborn errors of metabolism
title_short Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center
title_full Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center
title_fullStr Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center
title_full_unstemmed Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center
title_sort Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center
author Barbosa-Gouveia, Sofia
author_facet Barbosa-Gouveia, Sofia
Vázquez-Mosquera, María E.
González-Vioque, Emiliano
Álvarez, José V.
Chans, Roi
Laranjeira, Francisco
Martins, Esmeralda
Ferreira, Ana Cristina
Avila-Alvarez, Alejandro
Couce, María L.
author_role author
author2 Vázquez-Mosquera, María E.
González-Vioque, Emiliano
Álvarez, José V.
Chans, Roi
Laranjeira, Francisco
Martins, Esmeralda
Ferreira, Ana Cristina
Avila-Alvarez, Alejandro
Couce, María L.
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório Científico do Centro Hospitalar Universitário de Santo António
dc.contributor.author.fl_str_mv Barbosa-Gouveia, Sofia
Vázquez-Mosquera, María E.
González-Vioque, Emiliano
Álvarez, José V.
Chans, Roi
Laranjeira, Francisco
Martins, Esmeralda
Ferreira, Ana Cristina
Avila-Alvarez, Alejandro
Couce, María L.
dc.subject.por.fl_str_mv differential diagnosis
genetic diagnosis
inborn errors of metabolism
topic differential diagnosis
genetic diagnosis
inborn errors of metabolism
description Next-generation sequencing (NGS) technologies have been proposed as a first-line test for the diagnosis of inborn errors of metabolism (IEM), a group of genetically heterogeneous disorders with overlapping or nonspecific phenotypes. Over a 3-year period, we prospectively analyzed 311 pediatric patients with a suspected IEM using four targeted gene panels. The rate of positive diagnosis was 61.86% for intermediary metabolism defects, 32.84% for complex molecular defects, 19% for hypoglycemic/hyperglycemic events, and 17% for mitochondrial diseases, and a conclusive molecular diagnosis was established in 2-4 weeks. Forty-one patients for whom negative results were obtained with the mitochondrial diseases panel underwent subsequent analyses using the NeuroSeq panel, which groups all genes from the individual panels together with genes associated with neurological disorders (1870 genes in total). This achieved a diagnostic rate of 32%. We next evaluated the utility of a tool, Phenomizer, for differential diagnosis, and established a correlation between phenotype and molecular findings in 39.3% of patients. Finally, we evaluated the mutational architecture of the genes analyzed by determining z-scores, loss-of-function observed/expected upper bound fraction (LOEUF), and haploinsufficiency (HI) scores. In summary, targeted gene panels for specific groups of IEMs enabled rapid and effective diagnosis, which is critical for the therapeutic management of IEM patients.
publishDate 2021
dc.date.none.fl_str_mv 2021-08
2021-08-01T00:00:00Z
2023-10-24T09:16:35Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.16/2839
url http://hdl.handle.net/10400.16/2839
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Barbosa-Gouveia S, Vázquez-Mosquera ME, González-Vioque E, et al. Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center. Genes (Basel). 2021;12(8):1262. doi:10.3390/genes12081262
2073-4425
10.3390/genes12081262
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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