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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Bibliographic Details
Authors: 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.
Format: article
Publication Date:2019
Country:España
Institution:Servizo Galego de Saúde (SERGAS)
Repository:RUNA. Repositorio da Consellería de Sanidade e Sergas
OAI Identifier:oai:runa.sergas.gal:20.500.11940/15961
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919450/pdf/ct9-10-e00100.pdf
http://hdl.handle.net/20.500.11940/15961
Access Level:Open access
Keyword: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
Summary: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.

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