Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.16/2382 |
Resumo: | In order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis. |
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Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patientsde novo mutationsepilepsygenetic diagnosisincomplete penetrancemodifier genesneurodevelopmental disordersIn order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis.Frontiers MediaRepositório Científico do Centro Hospitalar Universitário de Santo AntónioFernández-Marmiesse, A.Roca, I.Díaz-Flores, F.Cantarín, V.Pérez-Poyato, M.Fontalba, A.Laranjeira, FranciscoQuintans, S.Moldovan, O.Felgueroso, B.Rodríguez-Pedreira, M.Simón, R.Camacho, A.Quijada, P.Ibanez-Mico, S.Domingno, M.Benito, C.Calvo, R.Pérez-Cejas, A.Carrasco, M.Ramos, F.Couce, M.Ruiz-Falcó, M.Gutierrez-Solana, L.Martínez-Atienza, M.2020-05-12T10:12:54Z20192019-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.16/2382engFernández-Marmiesse A, Roca I, Díaz-Flores F, et al. Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients. Front Neurosci. 2019;13:1135. Published 2019 Nov 8. doi:10.3389/fnins.2019.011351662-454810.3389/fnins.2019.01135info: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:RCAAP2023-10-20T11:00:31Zoai:repositorio.chporto.pt:10400.16/2382Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:38:35.152563Repositório 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 |
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients |
title |
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients |
spellingShingle |
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients Fernández-Marmiesse, A. de novo mutations epilepsy genetic diagnosis incomplete penetrance modifier genes neurodevelopmental disorders |
title_short |
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients |
title_full |
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients |
title_fullStr |
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients |
title_full_unstemmed |
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients |
title_sort |
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients |
author |
Fernández-Marmiesse, A. |
author_facet |
Fernández-Marmiesse, A. Roca, I. Díaz-Flores, F. Cantarín, V. Pérez-Poyato, M. Fontalba, A. Laranjeira, Francisco Quintans, S. Moldovan, O. Felgueroso, B. Rodríguez-Pedreira, M. Simón, R. Camacho, A. Quijada, P. Ibanez-Mico, S. Domingno, M. Benito, C. Calvo, R. Pérez-Cejas, A. Carrasco, M. Ramos, F. Couce, M. Ruiz-Falcó, M. Gutierrez-Solana, L. Martínez-Atienza, M. |
author_role |
author |
author2 |
Roca, I. Díaz-Flores, F. Cantarín, V. Pérez-Poyato, M. Fontalba, A. Laranjeira, Francisco Quintans, S. Moldovan, O. Felgueroso, B. Rodríguez-Pedreira, M. Simón, R. Camacho, A. Quijada, P. Ibanez-Mico, S. Domingno, M. Benito, C. Calvo, R. Pérez-Cejas, A. Carrasco, M. Ramos, F. Couce, M. Ruiz-Falcó, M. Gutierrez-Solana, L. Martínez-Atienza, M. |
author2_role |
author author author author author author author author author author author author author author author 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 |
Fernández-Marmiesse, A. Roca, I. Díaz-Flores, F. Cantarín, V. Pérez-Poyato, M. Fontalba, A. Laranjeira, Francisco Quintans, S. Moldovan, O. Felgueroso, B. Rodríguez-Pedreira, M. Simón, R. Camacho, A. Quijada, P. Ibanez-Mico, S. Domingno, M. Benito, C. Calvo, R. Pérez-Cejas, A. Carrasco, M. Ramos, F. Couce, M. Ruiz-Falcó, M. Gutierrez-Solana, L. Martínez-Atienza, M. |
dc.subject.por.fl_str_mv |
de novo mutations epilepsy genetic diagnosis incomplete penetrance modifier genes neurodevelopmental disorders |
topic |
de novo mutations epilepsy genetic diagnosis incomplete penetrance modifier genes neurodevelopmental disorders |
description |
In order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019 2019-01-01T00:00:00Z 2020-05-12T10:12:54Z |
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/10400.16/2382 |
url |
http://hdl.handle.net/10400.16/2382 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Fernández-Marmiesse A, Roca I, Díaz-Flores F, et al. Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients. Front Neurosci. 2019;13:1135. Published 2019 Nov 8. doi:10.3389/fnins.2019.01135 1662-4548 10.3389/fnins.2019.01135 |
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 |
Frontiers Media |
publisher.none.fl_str_mv |
Frontiers Media |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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