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 D, Hinarejos I, Argente-Escrig H, Marco-Marín C, Lozano MA, Gorría-Redondo N, Lupo V, Martí-Carrera I, Miranda C, Vázquez-López M, García-Pérez A, Marco-Hernández AV, Tomás-Vila M, Aguilera-Albesa S, Espinós C
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
Repositorio:r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:oai:fisabio.fundanetsuite.com:p16000
Acceso en línea:https://fisabio.portalinvestigacion.com/publicaciones/16000
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 DHinarejos IArgente-Escrig HMarco-Marín CLozano MAGorría-Redondo NLupo VMartí-Carrera IMiranda CVázquez-López MGarcía-Pérez AMarco-Hernández AVTomás-Vila MAguilera-Albesa SEspinós Cataxiacerebellar 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.MDPI2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/16000INTERNATIONAL JOURNAL OF MOLECULAR SCIENCESISSN: 16616596ISSNe: 14220067reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)Inglésinfo:eu-repo/semantics/openAccessoai:fisabio.fundanetsuite.com:p160002026-06-11T12:45:17Z
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 D
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 D
Hinarejos I
Argente-Escrig H
Marco-Marín C
Lozano MA
Gorría-Redondo N
Lupo V
Martí-Carrera I
Miranda C
Vázquez-López M
García-Pérez A
Marco-Hernández AV
Tomás-Vila M
Aguilera-Albesa S
Espinós C
author Martínez-Rubio D
author_facet Martínez-Rubio D
Hinarejos I
Argente-Escrig H
Marco-Marín C
Lozano MA
Gorría-Redondo N
Lupo V
Martí-Carrera I
Miranda C
Vázquez-López M
García-Pérez A
Marco-Hernández AV
Tomás-Vila M
Aguilera-Albesa S
Espinós C
author_role author
author2 Hinarejos I
Argente-Escrig H
Marco-Marín C
Lozano MA
Gorría-Redondo N
Lupo V
Martí-Carrera I
Miranda C
Vázquez-López M
García-Pérez A
Marco-Hernández AV
Tomás-Vila M
Aguilera-Albesa S
Espinós C
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
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
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fisabio.portalinvestigacion.com/publicaciones/16000
url https://fisabio.portalinvestigacion.com/publicaciones/16000
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN: 16616596
ISSNe: 14220067
reponame:r-FISABIO. Repositorio Institucional de Producción Científica
instname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
instname_str Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
reponame_str r-FISABIO. Repositorio Institucional de Producción Científica
collection r-FISABIO. Repositorio Institucional de Producción Científica
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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