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Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD

Genetic etiology in majority of patients with sporadic thoracic aortic aneurysm and dissections (STAAD) remains unknown. Recent GWAS study suggested common variant(s) in FBN1 is associated with STAAD. The present study aims to test this hypothesis and to identify mutation spectrum by targeted exome...

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Autores principales: Guo, Jun, Cai, Lun, Jia, Lixin, Li, Xiaoyan, Xi, Xin, Zheng, Shuai, Liu, Xuxia, Piao, Chunmei, Liu, Tingting, Sun, Zhongsheng, Cai, Tao, Du, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536522/
https://www.ncbi.nlm.nih.gov/pubmed/26272055
http://dx.doi.org/10.1038/srep13115
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author Guo, Jun
Cai, Lun
Jia, Lixin
Li, Xiaoyan
Xi, Xin
Zheng, Shuai
Liu, Xuxia
Piao, Chunmei
Liu, Tingting
Sun, Zhongsheng
Cai, Tao
Du, Jie
author_facet Guo, Jun
Cai, Lun
Jia, Lixin
Li, Xiaoyan
Xi, Xin
Zheng, Shuai
Liu, Xuxia
Piao, Chunmei
Liu, Tingting
Sun, Zhongsheng
Cai, Tao
Du, Jie
author_sort Guo, Jun
collection PubMed
description Genetic etiology in majority of patients with sporadic thoracic aortic aneurysm and dissections (STAAD) remains unknown. Recent GWAS study suggested common variant(s) in FBN1 is associated with STAAD. The present study aims to test this hypothesis and to identify mutation spectrum by targeted exome sequencing of the FBN1 gene in 146 unrelated patients with STAAD. Totally, 15.75% of FBN1 variants in STAAD were identified, including 5 disruptive and 18 missense mutations. Most of the variants were novel. Genotype-phenotype correlation analysis suggested that the maximum aortic diameter in the disruptive mutation group was significantly larger than that in the non-Cys missense mutation group. Interestingly, the variant Ala27Thr at −1 position, which is predicted to change the cleavage site of the signal peptidase of fibrillin-1, was detected in two unrelated patients. Furthermore, genotyping analysis of this variant detected 10 heterozygous Ala27Thr from additional 666 unrelated patients (1.50%), versus 7 from 1500 controls (0.47%), indicating a significant association of this variant with STAAD. Collectively, the identification of the variant Ala27Thr may represent a relatively common genetic predisposition and a novel pathogenetic mechanism for STAAD. Also, expansion of the mutation spectrum in FBN1 will be helpful in genetic counselling for Chinese patients with STAAD.
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spelling pubmed-45365222015-09-04 Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD Guo, Jun Cai, Lun Jia, Lixin Li, Xiaoyan Xi, Xin Zheng, Shuai Liu, Xuxia Piao, Chunmei Liu, Tingting Sun, Zhongsheng Cai, Tao Du, Jie Sci Rep Article Genetic etiology in majority of patients with sporadic thoracic aortic aneurysm and dissections (STAAD) remains unknown. Recent GWAS study suggested common variant(s) in FBN1 is associated with STAAD. The present study aims to test this hypothesis and to identify mutation spectrum by targeted exome sequencing of the FBN1 gene in 146 unrelated patients with STAAD. Totally, 15.75% of FBN1 variants in STAAD were identified, including 5 disruptive and 18 missense mutations. Most of the variants were novel. Genotype-phenotype correlation analysis suggested that the maximum aortic diameter in the disruptive mutation group was significantly larger than that in the non-Cys missense mutation group. Interestingly, the variant Ala27Thr at −1 position, which is predicted to change the cleavage site of the signal peptidase of fibrillin-1, was detected in two unrelated patients. Furthermore, genotyping analysis of this variant detected 10 heterozygous Ala27Thr from additional 666 unrelated patients (1.50%), versus 7 from 1500 controls (0.47%), indicating a significant association of this variant with STAAD. Collectively, the identification of the variant Ala27Thr may represent a relatively common genetic predisposition and a novel pathogenetic mechanism for STAAD. Also, expansion of the mutation spectrum in FBN1 will be helpful in genetic counselling for Chinese patients with STAAD. Nature Publishing Group 2015-08-14 /pmc/articles/PMC4536522/ /pubmed/26272055 http://dx.doi.org/10.1038/srep13115 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Guo, Jun
Cai, Lun
Jia, Lixin
Li, Xiaoyan
Xi, Xin
Zheng, Shuai
Liu, Xuxia
Piao, Chunmei
Liu, Tingting
Sun, Zhongsheng
Cai, Tao
Du, Jie
Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD
title Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD
title_full Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD
title_fullStr Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD
title_full_unstemmed Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD
title_short Wide mutation spectrum and frequent variant Ala27Thr of FBN1 identified in a large cohort of Chinese patients with sporadic TAAD
title_sort wide mutation spectrum and frequent variant ala27thr of fbn1 identified in a large cohort of chinese patients with sporadic taad
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536522/
https://www.ncbi.nlm.nih.gov/pubmed/26272055
http://dx.doi.org/10.1038/srep13115
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