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

Urbizu, Aintzane; Garrett, Melanie E.; Soldano, Karen; Drechsel, Oliver; Loth, Dorothy; Marcé-Grau, Anna; Mestres Soler, Olga; Poca, María A.; Ossowski, Stephan; Macaya, Alfons; Loth, Francis; Labuda, Rick; Ashley-Koch, Allison

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

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dc.contributor.author Urbizu, Aintzane
dc.contributor.author Garrett, Melanie E.
dc.contributor.author Soldano, Karen
dc.contributor.author Drechsel, Oliver
dc.contributor.author Loth, Dorothy
dc.contributor.author Marcé-Grau, Anna
dc.contributor.author Mestres Soler, Olga
dc.contributor.author Poca, María A.
dc.contributor.author Ossowski, Stephan
dc.contributor.author Macaya, Alfons
dc.contributor.author Loth, Francis
dc.contributor.author Labuda, Rick
dc.contributor.author Ashley-Koch, Allison
dc.date.accessioned 2021-07-14T07:01:15Z
dc.date.available 2021-07-14T07:01:15Z
dc.date.issued 2021
dc.description.abstract Chiari 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.
dc.description.sponsorship 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
dc.format.mimetype application/pdf
dc.identifier.citation Urbizu A, Garrett ME, Soldano K, Drechsel O, Loth D, Marcé-Grau A et al. Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1. PLoS One. 2021 May 11;16(5):e0251289. DOI: 10.1371/journal.pone.0251289
dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0251289
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/10230/48172
dc.language.iso eng
dc.publisher Public Library of Science (PLoS)
dc.rights © 2021 Ainnntzane Urbizu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject.other Deformitat d’Arnold-Chiari
dc.subject.other Genètica
dc.subject.other Neurologia
dc.title Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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