Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involv...

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Autores: Martínez-Rubio, Dolores, Hinarejos, Isabel, Argente-Escrig, Herminia, Marco-Marín, Clara, Lozano, María Ana, Gorría-Redondo, Nerea, Lupo, Vincenzo, Martí-Carrera, Itxaso, Miranda, Concepción, Vázquez-López, María, García-Pérez, Asunción, Marco-Hernández, Ana Victoria, Tomás-Vila, Miguel, Aguilera-Albesa, Sergio, Espinós, Carmen
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/340181
Acceso en línea:http://hdl.handle.net/10261/340181
Access Level:acceso abierto
Palabra clave:Ataxia
Cerebellar atrophy
Rare disease
Neuroimaging
Exome sequencing
Gene panel
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spelling Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar AtrophyMartínez-Rubio, DoloresHinarejos, IsabelArgente-Escrig, HerminiaMarco-Marín, ClaraLozano, María AnaGorría-Redondo, NereaLupo, VincenzoMartí-Carrera, ItxasoMiranda, ConcepciónVázquez-López, MaríaGarcía-Pérez, AsunciónMarco-Hernández, Ana VictoriaTomás-Vila, MiguelAguilera-Albesa, SergioEspinós, CarmenAtaxiaCerebellar atrophyRare diseaseNeuroimagingExome sequencingGene panelCerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity.This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project PI21/00103 to C.E. and co-funded by the European Union and through the grant FI19/00072 to I.H: co-funded by the European Union—European Social Fund (FSE). Part of the equipment employed in this work was funded by Generalitat Valenciana and co-financed with ERDF (OP ERDF of Comunitat Valenciana 2014–2020).Peer reviewedMultidisciplinary Digital Publishing InstituteInstituto de Salud Carlos IIIEuropean CommissionGeneralitat de CatalunyaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2023202320232023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/340181reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.3390/ijms242216400Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3401812026-05-22T06:33:51Z
dc.title.none.fl_str_mv Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy
title Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy
spellingShingle Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy
Martínez-Rubio, Dolores
Ataxia
Cerebellar atrophy
Rare disease
Neuroimaging
Exome sequencing
Gene panel
title_short Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy
title_full Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy
title_fullStr Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy
title_full_unstemmed Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy
title_sort Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy
dc.creator.none.fl_str_mv Martínez-Rubio, Dolores
Hinarejos, Isabel
Argente-Escrig, Herminia
Marco-Marín, Clara
Lozano, María Ana
Gorría-Redondo, Nerea
Lupo, Vincenzo
Martí-Carrera, Itxaso
Miranda, Concepción
Vázquez-López, María
García-Pérez, Asunción
Marco-Hernández, Ana Victoria
Tomás-Vila, Miguel
Aguilera-Albesa, Sergio
Espinós, Carmen
author Martínez-Rubio, Dolores
author_facet Martínez-Rubio, Dolores
Hinarejos, Isabel
Argente-Escrig, Herminia
Marco-Marín, Clara
Lozano, María Ana
Gorría-Redondo, Nerea
Lupo, Vincenzo
Martí-Carrera, Itxaso
Miranda, Concepción
Vázquez-López, María
García-Pérez, Asunción
Marco-Hernández, Ana Victoria
Tomás-Vila, Miguel
Aguilera-Albesa, Sergio
Espinós, Carmen
author_role author
author2 Hinarejos, Isabel
Argente-Escrig, Herminia
Marco-Marín, Clara
Lozano, María Ana
Gorría-Redondo, Nerea
Lupo, Vincenzo
Martí-Carrera, Itxaso
Miranda, Concepción
Vázquez-López, María
García-Pérez, Asunción
Marco-Hernández, Ana Victoria
Tomás-Vila, Miguel
Aguilera-Albesa, Sergio
Espinós, Carmen
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Generalitat de Catalunya
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Ataxia
Cerebellar atrophy
Rare disease
Neuroimaging
Exome sequencing
Gene panel
topic Ataxia
Cerebellar atrophy
Rare disease
Neuroimaging
Exome sequencing
Gene panel
description Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/340181
url http://hdl.handle.net/10261/340181
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.3390/ijms242216400
Sí
dc.rights.none.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 Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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