Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1

Seqüenciació de gens; Genòmica; Imatges per ressonància magnètica

Detalhes bibliográficos
Autores: Urbizu, Aintzane, Garrett, Melanie E., Soldano, Karen, Drechsel, Oliver, Loth, Dorothy, Marcé Grau, Anna, Poca Pastor, Ma Antonia, Mestres Soler, Olga, Macaya Ruíz, Alfons
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Departament de Salut de la Generalitat de Catalunya (DS)
Repositorio:Scientia. Dipòsit d'Informació Digital del Departament de Salut
OAI Identifier:oai:scientiasalut.gencat.cat:11351/6738
Acesso em linha:https://hdl.handle.net/11351/6738
Access Level:acceso abierto
Palavra-chave:Tub neural - Malformacions
Genòmica
DISEASES::Nervous System Diseases::Nervous System Malformations::Neural Tube Defects::Arnold-Chiari Malformation
Other subheadings::Other subheadings::Other subheadings::/genetics
PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation
ENFERMEDADES::enfermedades del sistema nervioso::malformaciones del sistema nervioso::defectos del tubo neural::malformación de Arnold-Chiari
Otros calificadores::Otros calificadores::Otros calificadores::/genética
FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética
id ES_a8a78bd7a30ea7fdce9c1f22fd6f7354
oai_identifier_str oai:scientiasalut.gencat.cat:11351/6738
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1
title Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1
spellingShingle Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1
Urbizu, Aintzane
Tub neural - Malformacions
Genòmica
DISEASES::Nervous System Diseases::Nervous System Malformations::Neural Tube Defects::Arnold-Chiari Malformation
Other subheadings::Other subheadings::Other subheadings::/genetics
PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation
ENFERMEDADES::enfermedades del sistema nervioso::malformaciones del sistema nervioso::defectos del tubo neural::malformación de Arnold-Chiari
Otros calificadores::Otros calificadores::Otros calificadores::/genética
FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética
title_short Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1
title_full Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1
title_fullStr Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1
title_full_unstemmed Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1
title_sort Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1
dc.creator.none.fl_str_mv Urbizu, Aintzane
Garrett, Melanie E.
Soldano, Karen
Drechsel, Oliver
Loth, Dorothy
Marcé Grau, Anna
Poca Pastor, Ma Antonia
Mestres Soler, Olga
Macaya Ruíz, Alfons
author Urbizu, Aintzane
author_facet Urbizu, Aintzane
Garrett, Melanie E.
Soldano, Karen
Drechsel, Oliver
Loth, Dorothy
Marcé Grau, Anna
Poca Pastor, Ma Antonia
Mestres Soler, Olga
Macaya Ruíz, Alfons
author_role author
author2 Garrett, Melanie E.
Soldano, Karen
Drechsel, Oliver
Loth, Dorothy
Marcé Grau, Anna
Poca Pastor, Ma Antonia
Mestres Soler, Olga
Macaya Ruíz, Alfons
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Institut Català de la Salut
[Urbizu A] Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States of America. Grup de Recerca en Neurologia Pediàtrica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Garrett ME, Soldano K] Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States of America. [Drechsel O] Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain. Universitat Pompeu Fabra, Barcelona, Spain. [Loth D] Department of Psychology, Conquer Chiari Research Center, University of Akron, Akron, OH, United States of America. [Marcé-Grau A, Macaya A] Grup de Recerca en Neurologia Pediàtrica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Mestres I Soler O] Unitat de Recerca en Neurotraumatologia i Neurocirurgia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Poca MA] Unitat de Recerca en Neurotraumatologia i Neurocirurgia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Neurocirurgia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain
Vall d'Hebron Barcelona Hospital Campus
dc.subject.none.fl_str_mv Tub neural - Malformacions
Genòmica
DISEASES::Nervous System Diseases::Nervous System Malformations::Neural Tube Defects::Arnold-Chiari Malformation
Other subheadings::Other subheadings::Other subheadings::/genetics
PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation
ENFERMEDADES::enfermedades del sistema nervioso::malformaciones del sistema nervioso::defectos del tubo neural::malformación de Arnold-Chiari
Otros calificadores::Otros calificadores::Otros calificadores::/genética
FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética
topic Tub neural - Malformacions
Genòmica
DISEASES::Nervous System Diseases::Nervous System Malformations::Neural Tube Defects::Arnold-Chiari Malformation
Other subheadings::Other subheadings::Other subheadings::/genetics
PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation
ENFERMEDADES::enfermedades del sistema nervioso::malformaciones del sistema nervioso::defectos del tubo neural::malformación de Arnold-Chiari
Otros calificadores::Otros calificadores::Otros calificadores::/genética
FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética
description Seqüenciació de gens; Genòmica; Imatges per ressonància magnètica
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
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://hdl.handle.net/11351/6738
url https://hdl.handle.net/11351/6738
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv PLoS One;16(5)
https://doi.org/10.1371/journal.pone.0251289
dc.rights.none.fl_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library Science
publisher.none.fl_str_mv Public Library Science
dc.source.none.fl_str_mv Scientia
reponame:Scientia. Dipòsit d'Informació Digital del Departament de Salut
instname:Departament de Salut de la Generalitat de Catalunya (DS)
instname_str Departament de Salut de la Generalitat de Catalunya (DS)
reponame_str Scientia. Dipòsit d'Informació Digital del Departament de Salut
collection Scientia. Dipòsit d'Informació Digital del Departament de Salut
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869415916734775296
spelling Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1Urbizu, AintzaneGarrett, Melanie E.Soldano, KarenDrechsel, OliverLoth, DorothyMarcé Grau, AnnaPoca Pastor, Ma AntoniaMestres Soler, OlgaMacaya Ruíz, AlfonsTub neural - MalformacionsGenòmicaDISEASES::Nervous System Diseases::Nervous System Malformations::Neural Tube Defects::Arnold-Chiari MalformationOther subheadings::Other subheadings::Other subheadings::/geneticsPHENOMENA AND PROCESSES::Genetic Phenomena::Genetic VariationENFERMEDADES::enfermedades del sistema nervioso::malformaciones del sistema nervioso::defectos del tubo neural::malformación de Arnold-ChiariOtros calificadores::Otros calificadores::Otros calificadores::/genéticaFENÓMENOS Y PROCESOS::fenómenos genéticos::variación genéticaSeqüenciació de gens; Genòmica; Imatges per ressonància magnèticaSecuenciación de genes; Genómica; Imágenes por resonancia magnéticaGene sequencing; Genomics; Magnetic resonance imagingChiari Malformation Type 1 (CM-1) is characterized by herniation of the cerebellar tonsils below the foramen magnum and the presence of headaches and other neurologic symptoms. Cranial bone constriction is suspected to be the most common biologic mechanism leading to CM-1. However, other mechanisms may also contribute, particularly in the presence of connective tissue disorders (CTDs), such as Ehlers Danlos Syndrome (EDS). Accumulating data suggest CM-1 with connective tissue disorders (CTD+) may have a different patho-mechanism and different genetic risk factors than CM-1 without CTDs (CTD-). To identify CM-1 genetic risk variants, we performed whole exome sequencing on a single large, multiplex family from Spain and targeted sequencing on a cohort of 186 unrelated adult, Caucasian females with CM-1. Targeted sequencing captured the coding regions of 21 CM-1 and EDS candidate genes, including two genes identified in the Spanish family. Using gene burden analysis, we compared the frequency of rare, functional variants detected in CM-1 cases versus publically available ethnically-matched controls from gnomAD. A secondary analysis compared the presence of rare variants in these genes between CTD+ and CTD- CM-1 cases. In the Spanish family, rare variants co-segregated with CM-1 in COL6A5, ADGRB3 and DST. A variant in COL7A1 was present in affected and unaffected family members. In the targeted sequencing analysis, rare variants in six genes (COL7A1, COL5A2, COL6A5, COL1A2, VEGFB, FLT1) were significantly more frequent in CM-1 cases compared to public controls. In total, 47% of CM-1 cases presented with rare variants in at least one of the four significant collagen genes and 10% of cases harbored variants in multiple significant collagen genes. Moreover, 26% of CM-1 cases presented with rare variants in the COL6A5 gene. We also identified two genes (COL7A1, COL3A1) for which the burden of rare variants differed significantly between CTD+ and CTD- CM-1 cases. A higher percentage of CTD+ patients had variants in COL7A1 compared to CTD+ patients, while CTD+ patients had fewer rare variants in COL3A1 than did CTD- patients. In summary, rare variants in several collagen genes are particularly frequent in CM-1 cases and those in COL6A5 co-segregated with CM-1 in a Spanish multiplex family. COL6A5 has been previously associated with musculoskeletal phenotypes, but this is the first association with CM-1. Our findings underscore the contribution of rare genetic variants in collagen genes to CM-1, and suggest that CM-1 in the presence and absence of CTD symptoms is driven by different genes.This work was supported by a grant from Conquer Chiari to AAK. Collection of the Chiari1000 study participants utilized in this study was supported by a grant from Conquer Chiari to FL at University of Akron. Collection of the Duke study participants utilized in this study was supported by a grant from the National Institutes of Health (NS063273). A.U. was the recipient of a Postdoctoral Fellowship from Fundación Ramón Areces (Spain). RL is the Executive Director of Conquer Chiari which provided some of the funding for this work. For the manuscript, he assisted with revising and editing the manuscript. The funders did have a role in study design, but had no role in data collection and analysis, decision to publish, or preparation of the manuscript.Public Library ScienceInstitut Català de la Salut[Urbizu A] Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States of America. Grup de Recerca en Neurologia Pediàtrica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Garrett ME, Soldano K] Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States of America. [Drechsel O] Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain. Universitat Pompeu Fabra, Barcelona, Spain. [Loth D] Department of Psychology, Conquer Chiari Research Center, University of Akron, Akron, OH, United States of America. [Marcé-Grau A, Macaya A] Grup de Recerca en Neurologia Pediàtrica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Mestres I Soler O] Unitat de Recerca en Neurotraumatologia i Neurocirurgia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Poca MA] Unitat de Recerca en Neurotraumatologia i Neurocirurgia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Neurocirurgia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, SpainVall d'Hebron Barcelona Hospital Campus202120212021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttps://hdl.handle.net/11351/6738Scientiareponame:Scientia. Dipòsit d'Informació Digital del Departament de Salutinstname:Departament de Salut de la Generalitat de Catalunya (DS)InglésPLoS One;16(5)https://doi.org/10.1371/journal.pone.0251289Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:scientiasalut.gencat.cat:11351/67382026-06-12T09:38:37Z
score 15.812455

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