Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing

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...

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Autores: Toma, C., Diaz-Gay, M., Soares de Lima, Y., Arnau-Collell, C., Franch-Exposito, S., Munoz, J., Overs, B., Bonjoch, L., Carballal, S., Ocana, T., Cuatrecasas, M., Diaz de Bustamante, A., Castells, A., Bujanda, L., Cubiella Fernández, Joaquín, Balaguer, F., Rodriguez-Alcalde, D., Fullerton, J. M., Castellvi-Bel, S.
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Servizo Galego de Saúde (SERGAS)
Repositorio:RUNA. Repositorio da Consellería de Sanidade e Sergas
OAI Identifier:oai:runa.sergas.gal:20.500.11940/15961
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919450/pdf/ct9-10-e00100.pdf
http://hdl.handle.net/20.500.11940/15961
Access Level:acceso abierto
Palabra clave:Genetic Counseling
Extracellular Matrix Proteins
Adult
Middle Aged
Humans
Young Adult
Calcium-Binding Proteins
Adenomatous Polyposis Coli
Genetic Predisposition to Disease
Aged
Genetic Linkage
ligamiento genético
consejo genético
poliposis adenomatosa del colon
anciano
proteínas de la matriz extracelular
adulto joven
mediana edad
humanos
adulto
predisposición genética a la enfermedad
proteínas de unión al calcio
CHUO
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oai_identifier_str oai:runa.sergas.gal:20.500.11940/15961
network_acronym_str ES
network_name_str España
repository_id_str
spelling Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome SequencingToma, C.Diaz-Gay, M.Soares de Lima, Y.Arnau-Collell, C.Franch-Exposito, S.Munoz, J.Overs, B.Bonjoch, L.Carballal, S.Ocana, T.Cuatrecasas, M.Diaz de Bustamante, A.Castells, A.Bujanda, L.Cubiella Fernández, JoaquínBalaguer, F.Rodriguez-Alcalde, D.Fullerton, J. M.Castellvi-Bel, S.Genetic CounselingExtracellular Matrix ProteinsAdultMiddle AgedHumansYoung AdultCalcium-Binding ProteinsAdenomatous Polyposis ColiGenetic Predisposition to DiseaseAgedGenetic Linkageligamiento genéticoconsejo genéticopoliposis adenomatosa del colonancianoproteínas de la matriz extracelularadulto jovenmediana edadhumanosadultopredisposición genética a la enfermedadproteínas de unión al calcioCHUOOBJECTIVES: 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: A 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 P value > 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.2019info:eu-repo/semantics/articlehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919450/pdf/ct9-10-e00100.pdfhttp://hdl.handle.net/20.500.11940/15961reponame:RUNA. Repositorio da Consellería de Sanidade e Sergasinstname:Servizo Galego de Saúde (SERGAS)Ingléshttps://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:runa.sergas.gal:20.500.11940/159612026-06-12T08:40:47Z
dc.title.none.fl_str_mv Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing
title Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing
spellingShingle Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing
Toma, C.
Genetic Counseling
Extracellular Matrix Proteins
Adult
Middle Aged
Humans
Young Adult
Calcium-Binding Proteins
Adenomatous Polyposis Coli
Genetic Predisposition to Disease
Aged
Genetic Linkage
ligamiento genético
consejo genético
poliposis adenomatosa del colon
anciano
proteínas de la matriz extracelular
adulto joven
mediana edad
humanos
adulto
predisposición genética a la enfermedad
proteínas de unión al calcio
CHUO
title_short Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing
title_full Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing
title_fullStr Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing
title_full_unstemmed Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing
title_sort Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing
dc.creator.none.fl_str_mv Toma, C.
Diaz-Gay, M.
Soares de Lima, Y.
Arnau-Collell, C.
Franch-Exposito, S.
Munoz, J.
Overs, B.
Bonjoch, L.
Carballal, S.
Ocana, T.
Cuatrecasas, M.
Diaz de Bustamante, A.
Castells, A.
Bujanda, L.
Cubiella Fernández, Joaquín
Balaguer, F.
Rodriguez-Alcalde, D.
Fullerton, J. M.
Castellvi-Bel, S.
author Toma, C.
author_facet Toma, C.
Diaz-Gay, M.
Soares de Lima, Y.
Arnau-Collell, C.
Franch-Exposito, S.
Munoz, J.
Overs, B.
Bonjoch, L.
Carballal, S.
Ocana, T.
Cuatrecasas, M.
Diaz de Bustamante, A.
Castells, A.
Bujanda, L.
Cubiella Fernández, Joaquín
Balaguer, F.
Rodriguez-Alcalde, D.
Fullerton, J. M.
Castellvi-Bel, S.
author_role author
author2 Diaz-Gay, M.
Soares de Lima, Y.
Arnau-Collell, C.
Franch-Exposito, S.
Munoz, J.
Overs, B.
Bonjoch, L.
Carballal, S.
Ocana, T.
Cuatrecasas, M.
Diaz de Bustamante, A.
Castells, A.
Bujanda, L.
Cubiella Fernández, Joaquín
Balaguer, F.
Rodriguez-Alcalde, D.
Fullerton, J. M.
Castellvi-Bel, S.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Genetic Counseling
Extracellular Matrix Proteins
Adult
Middle Aged
Humans
Young Adult
Calcium-Binding Proteins
Adenomatous Polyposis Coli
Genetic Predisposition to Disease
Aged
Genetic Linkage
ligamiento genético
consejo genético
poliposis adenomatosa del colon
anciano
proteínas de la matriz extracelular
adulto joven
mediana edad
humanos
adulto
predisposición genética a la enfermedad
proteínas de unión al calcio
CHUO
topic Genetic Counseling
Extracellular Matrix Proteins
Adult
Middle Aged
Humans
Young Adult
Calcium-Binding Proteins
Adenomatous Polyposis Coli
Genetic Predisposition to Disease
Aged
Genetic Linkage
ligamiento genético
consejo genético
poliposis adenomatosa del colon
anciano
proteínas de la matriz extracelular
adulto joven
mediana edad
humanos
adulto
predisposición genética a la enfermedad
proteínas de unión al calcio
CHUO
description 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: A 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 P value > 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919450/pdf/ct9-10-e00100.pdf
http://hdl.handle.net/20.500.11940/15961
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919450/pdf/ct9-10-e00100.pdf
http://hdl.handle.net/20.500.11940/15961
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:RUNA. Repositorio da Consellería de Sanidade e Sergas
instname:Servizo Galego de Saúde (SERGAS)
instname_str Servizo Galego de Saúde (SERGAS)
reponame_str RUNA. Repositorio da Consellería de Sanidade e Sergas
collection RUNA. Repositorio da Consellería de Sanidade e Sergas
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300724

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