Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing
dc.contributor.author | Toma, Claudio | |
dc.contributor.author | Díaz Gay, Marcos | |
dc.contributor.author | Soares de Lima, Yasmin | |
dc.contributor.author | Arnau Collell, Coral | |
dc.contributor.author | Franch Expósito, Sebastià | |
dc.contributor.author | Muñoz, Jenifer | |
dc.contributor.author | Overs, Bronwyn | |
dc.contributor.author | Bonjoch, Laia | |
dc.contributor.author | Carballal, Sabela | |
dc.contributor.author | Ocaña, Teresa | |
dc.contributor.author | Cuatrecasas, Miriam | |
dc.contributor.author | Díaz de Bustamante, Aranzazu | |
dc.contributor.author | Castells, Antoni | |
dc.contributor.author | Bujanda Fernández de Pierola, Luis | |
dc.contributor.author | Cubiella, Joaquín | |
dc.contributor.author | Balaguer, Francesc | |
dc.contributor.author | Rodríguez Alcalde, Daniel | |
dc.contributor.author | Fullerton, Janice M. | |
dc.contributor.author | Castellví-Bel, Sergi | |
dc.date.accessioned | 2020-01-21T08:37:14Z | |
dc.date.available | 2020-01-21T08:37:14Z | |
dc.date.issued | 2019-09-19 | |
dc.identifier.citation | Clinical and Translational Gastroenterology 10(10) : (2019) // Article ID e00100 | es_ES |
dc.identifier.issn | 2155-384X | |
dc.identifier.uri | http://hdl.handle.net/10810/39065 | |
dc.description | SUPPLEMENTARY MATERIAL accompanies this paper athttp://links.lww.com/CTG/A114 | es_ES |
dc.description.abstract | OBJECTIVES: Serrated polyposis syndrome (SPS) is a complex disorder with a high risk of colorectal cancer for which the germline factors remain largely unknown. Here, we combined whole-exome sequencing (WES) and linkage studies in families with multiple members affected by SPS to identify candidate genes harboring rare variants with higher penetrance effects. METHODS: Thirty-nine affected subjects from 16 extended SPS families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. The contribution of rare coding variants selected to be highly pathogenic was assessed using the gene-based segregation test. RESULTS: significant linkage peak was identified on chromosome 3p25.2-p22.3 (maxSNP = rs2293787; LODlinear = 2.311, LODexp = 2.11), which logarithm of the odds (LOD) score increased after fine mapping for the same marker (maxSNP = rs2293787; LODlinear = 2.4, LODexp = 2.25). This linkage signal was replicated in 10 independent sets of random markers from this locus. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 11 rare variants predicted to be deleterious from 10 genes under the linkage intervals. This analysis showed significant segregation of rare variants with SPS in CAPT7, TMEM43, NGLY1, and FBLN2 genes (weighted Pvalue > 0.007). DISCUSSION: Protein network analysis suggested FBLN2 as the most plausible candidate genes for germline SPS predisposition. Etiologic rare variants implicated in disease predisposition may be identified by combining traditional linkage with WES data. This powerful approach was effective for the identification of a new candidate gene for hereditary SPS. | es_ES |
dc.description.sponsorship | M.D.-G. was supported by a contract from Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (Generalitat de Catalunya, 2018FI_B1_00213). S.F.-E., C.A.-C. and J.M. were supported by a contract from CIBEREHD. Y.S.L. was supported by a fellowship (LCF/BQ/DI18/11660058) from "la Caixa" Foundation (ID 100010434) funded EU Horizon 2020 Programme (Marie Sklodowska-Curie grant agreement no. 713673). LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). CIBEREHD and CIBERONC are funded by the Instituto de Salud Carlos III. CT, BJO, and JMF were supported by Australian National Health and Medical Research (NHMRC) Project Grants 1063960 and 1066177. This research was supported by grants from Fondo de Investigacion Sanitaria/FEDER (16/00766, 17/00878), Fundacion Cientifica de la Asociacion Espanola contra el Cancer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya), and Agencia de Gestio d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653). This article is based on work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology). www.cost.eu.Potential competing interests: None to report. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Lippincott Williams & Wilkins | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.subject | colorectal-cancer | es_ES |
dc.subject | rnf43 mutations | es_ES |
dc.subject | rare variants | es_ES |
dc.subject | pathway | es_ES |
dc.subject | families | es_ES |
dc.subject | locus | es_ES |
dc.title | Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology. Open AccessThis is an open-access article distributed under the terms of theCreative Commons Attribution-Non Commercial-No Derivatives License 4.0(CCBY-NC-ND), where it is permissible to download and share the work pro-vided it is properly cited. The work cannot be changed in any way or usedcommercially without permission from the journal. | es_ES |
dc.rights.holder | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.relation.publisherversion | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919450/ | es_ES |
dc.identifier.doi | 10.14309/ctg.0000000000000100 | |
dc.departamentoes | Medicina | es_ES |
dc.departamentoeu | Medikuntza | es_ES |
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Except where otherwise noted, this item's license is described as © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.
Open AccessThis is an open-access article distributed under the terms of theCreative Commons Attribution-Non Commercial-No Derivatives License 4.0(CCBY-NC-ND), where it is permissible to download and share the work pro-vided it is properly cited. The work cannot be changed in any way or usedcommercially without permission from the journal.