Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients
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 i...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2019-11-01
|
Series: | Frontiers in Neuroscience |
Subjects: | |
Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.01135/full |
id |
doaj-9472500101a14f7eb251f61423ea1fb9 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ana Fernández-Marmiesse Ana Fernández-Marmiesse Iria Roca Iria Roca Felícitas Díaz-Flores Verónica Cantarín Mª Socorro Pérez-Poyato Ana Fontalba Francisco Laranjeira Sofia Quintans Oana Moldovan Blanca Felgueroso Montserrat Rodríguez-Pedreira Rogelio Simón Ana Camacho Ana Camacho Pilar Quijada Salvador Ibanez-Mico Mª Rosario Domingno Carmen Benito Rocío Calvo Antonia Pérez-Cejas Mª Llanos Carrasco Feliciano Ramos Mª Luz Couce Mª Luz Ruiz-Falcó Luis Gutierrez-Solana Margarita Martínez-Atienza Margarita Martínez-Atienza Margarita Martínez-Atienza |
spellingShingle |
Ana Fernández-Marmiesse Ana Fernández-Marmiesse Iria Roca Iria Roca Felícitas Díaz-Flores Verónica Cantarín Mª Socorro Pérez-Poyato Ana Fontalba Francisco Laranjeira Sofia Quintans Oana Moldovan Blanca Felgueroso Montserrat Rodríguez-Pedreira Rogelio Simón Ana Camacho Ana Camacho Pilar Quijada Salvador Ibanez-Mico Mª Rosario Domingno Carmen Benito Rocío Calvo Antonia Pérez-Cejas Mª Llanos Carrasco Feliciano Ramos Mª Luz Couce Mª Luz Ruiz-Falcó Luis Gutierrez-Solana Margarita Martínez-Atienza Margarita Martínez-Atienza Margarita Martínez-Atienza Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients Frontiers in Neuroscience epilepsy genetic diagnosis neurodevelopmental disorders de novo mutations incomplete penetrance modifier genes |
author_facet |
Ana Fernández-Marmiesse Ana Fernández-Marmiesse Iria Roca Iria Roca Felícitas Díaz-Flores Verónica Cantarín Mª Socorro Pérez-Poyato Ana Fontalba Francisco Laranjeira Sofia Quintans Oana Moldovan Blanca Felgueroso Montserrat Rodríguez-Pedreira Rogelio Simón Ana Camacho Ana Camacho Pilar Quijada Salvador Ibanez-Mico Mª Rosario Domingno Carmen Benito Rocío Calvo Antonia Pérez-Cejas Mª Llanos Carrasco Feliciano Ramos Mª Luz Couce Mª Luz Ruiz-Falcó Luis Gutierrez-Solana Margarita Martínez-Atienza Margarita Martínez-Atienza Margarita Martínez-Atienza |
author_sort |
Ana Fernández-Marmiesse |
title |
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients |
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 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neuroscience |
issn |
1662-453X |
publishDate |
2019-11-01 |
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. |
topic |
epilepsy genetic diagnosis neurodevelopmental disorders de novo mutations incomplete penetrance modifier genes |
url |
https://www.frontiersin.org/article/10.3389/fnins.2019.01135/full |
work_keys_str_mv |
AT anafernandezmarmiesse rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT anafernandezmarmiesse rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT iriaroca rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT iriaroca rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT felicitasdiazflores rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT veronicacantarin rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT masocorroperezpoyato rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT anafontalba rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT franciscolaranjeira rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT sofiaquintans rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT oanamoldovan rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT blancafelgueroso rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT montserratrodriguezpedreira rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT rogeliosimon rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT anacamacho rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT anacamacho rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT pilarquijada rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT salvadoribanezmico rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT marosariodomingno rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT carmenbenito rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT rociocalvo rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT antoniaperezcejas rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT mallanoscarrasco rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT felicianoramos rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT maluzcouce rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT maluzruizfalco rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT luisgutierrezsolana rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT margaritamartinezatienza rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT margaritamartinezatienza rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients AT margaritamartinezatienza rarevariantsin48genesaccountfor42ofcasesofepilepsywithorwithoutneurodevelopmentaldelayin246pediatricpatients |
_version_ |
1724948954890633216 |
spelling |
doaj-9472500101a14f7eb251f61423ea1fb92020-11-25T02:03:10ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-11-011310.3389/fnins.2019.01135480017Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric PatientsAna Fernández-Marmiesse0Ana Fernández-Marmiesse1Iria Roca2Iria Roca3Felícitas Díaz-Flores4Verónica Cantarín5Mª Socorro Pérez-Poyato6Ana Fontalba7Francisco Laranjeira8Sofia Quintans9Oana Moldovan10Blanca Felgueroso11Montserrat Rodríguez-Pedreira12Rogelio Simón13Ana Camacho14Ana Camacho15Pilar Quijada16Salvador Ibanez-Mico17Mª Rosario Domingno18Carmen Benito19Rocío Calvo20Antonia Pérez-Cejas21Mª Llanos Carrasco22Feliciano Ramos23Mª Luz Couce24Mª Luz Ruiz-Falcó25Luis Gutierrez-Solana26Margarita Martínez-Atienza27Margarita Martínez-Atienza28Margarita Martínez-Atienza29Unit for the Diagnosis and Treatment of Congenital Metabolic Diseases, Clinical University Hospital of Santiago de Compostela, Health Research Institute of Santiago de Compostela, Santiago de Compostela, SpainGenomes & Disease Group, Molecular Medicine and Chronic Diseases Research Centre (CiMUS), Santiago de Compostela University–IDIS, Santiago de Compostela, SpainUnit for the Diagnosis and Treatment of Congenital Metabolic Diseases, Clinical University Hospital of Santiago de Compostela, Health Research Institute of Santiago de Compostela, Santiago de Compostela, SpainGenomes & Disease Group, Molecular Medicine and Chronic Diseases Research Centre (CiMUS), Santiago de Compostela University–IDIS, Santiago de Compostela, SpainMolecular Genetics Unit, Clinical University Hospital of Canarias, Santa Cruz de Tenerife, SpainNeuropediatrics Unit, Niño Jesús Clinical University Hospital, Madrid, SpainNeuropediatrics Unit, Marqués de Valdecilla Clinical University Hospital, Santander, SpainGenetics Unit, Marqués de Valdecilla Clinical University Hospital, Santander, SpainCentro de Genética Médica Jacinto Magalhães, Centro Hospitalar Do Porto, Porto, PortugalNeuropediatrics Unit, Santa María Hospital, Lisbon, PortugalGenetics Unit, Santa María Hospital, Lisbon, Portugal0Neuropediatrics Unit, Teresa Herrera Child's Hospital, A Coruña, Spain1Clinical Genetics Unit, Teresa Herrera Child's Hospital, A Coruña, Spain2Neuropediatrics Unit, 12 de Octubre Clinical University Hospital, Madrid, Spain2Neuropediatrics Unit, 12 de Octubre Clinical University Hospital, Madrid, Spain3Department of Medicine, Complutense University of Madrid, Madrid, Spain4Metabolic Disorders Unit, 12 de Octubre Clinical University Hospital, Madrid, Spain5Neuropediatrics Unit, Virgen de la Arrixaca Clinical University Hospital, Murcia, Spain5Neuropediatrics Unit, Virgen de la Arrixaca Clinical University Hospital, Murcia, Spain6Genetics Unit, Clinical University Hospital of Málaga, Málaga, Spain7Neuropediatrics Unit, Clinical University Hospital of Málaga, Málaga, SpainMolecular Genetics Unit, Clinical University Hospital of Canarias, Santa Cruz de Tenerife, Spain8Neuropediatrics Unit, Clinical University Hospital Severo Ochoa, Leganés, Madrid, Spain9Clinical Genetics Unit, Pediatrics, Clinical University Hospital of Zaragoza, Zaragoza, SpainUnit for the Diagnosis and Treatment of Congenital Metabolic Diseases, Clinical University Hospital of Santiago de Compostela, Health Research Institute of Santiago de Compostela, Santiago de Compostela, SpainNeuropediatrics Unit, Niño Jesús Clinical University Hospital, Madrid, SpainNeuropediatrics Unit, Niño Jesús Clinical University Hospital, Madrid, SpainGenomes & Disease Group, Molecular Medicine and Chronic Diseases Research Centre (CiMUS), Santiago de Compostela University–IDIS, Santiago de Compostela, SpainMolecular Genetics Unit, Clinical University Hospital of Canarias, Santa Cruz de Tenerife, Spain0Molecular Genetics Unit, Virgen de las Nieves Clinical University Hospital, Granada, SpainIn 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.https://www.frontiersin.org/article/10.3389/fnins.2019.01135/fullepilepsygenetic diagnosisneurodevelopmental disordersde novo mutationsincomplete penetrancemodifier genes |