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Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome

BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel gene...

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Autores principales: Pu, Zhening, Sun, Haoliang, Du, Junjie, Cheng, Yue, He, Keshuai, Ni, Buqing, Gu, Weidong, Dai, Juncheng, Shao, Yongfeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238762/
https://www.ncbi.nlm.nih.gov/pubmed/30479897
http://dx.doi.org/10.7717/peerj.5927
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author Pu, Zhening
Sun, Haoliang
Du, Junjie
Cheng, Yue
He, Keshuai
Ni, Buqing
Gu, Weidong
Dai, Juncheng
Shao, Yongfeng
author_facet Pu, Zhening
Sun, Haoliang
Du, Junjie
Cheng, Yue
He, Keshuai
Ni, Buqing
Gu, Weidong
Dai, Juncheng
Shao, Yongfeng
author_sort Pu, Zhening
collection PubMed
description BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel genetic variants in determining MFS clinical phenotypes. METHODS: We sequenced the whole exome of 19 individuals derived from three Han Chinese families. The sequencing data were analyzed by a standard pipeline. Variants were further filtered against the public database and an in-house database. Then, we performed pedigree analysis under different inheritance patterns according to American College of Medical Genetics guidelines. Results were confirmed by Sanger sequencing. RESULTS: Two novel loss-of-function indels (c.5027_5028insTGTCCTCC, p.D1677Vfs*8; c.5856delG, p.S1953Lfs*27) and one nonsense variant (c.8034C>A, p.Y2678*) of FBN1 were identified in Family 1, Family 2 and Family 3, respectively. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of FBN1 were located in the cbEGF region and a conserved domain across species and were not reported previously. CONCLUSIONS: Our study extended and strengthened the vital role of FBN1 LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation-based pre- and postnatal screening, genetic diagnosis and clinical management for MFS.
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spelling pubmed-62387622018-11-26 Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome Pu, Zhening Sun, Haoliang Du, Junjie Cheng, Yue He, Keshuai Ni, Buqing Gu, Weidong Dai, Juncheng Shao, Yongfeng PeerJ Genetics BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel genetic variants in determining MFS clinical phenotypes. METHODS: We sequenced the whole exome of 19 individuals derived from three Han Chinese families. The sequencing data were analyzed by a standard pipeline. Variants were further filtered against the public database and an in-house database. Then, we performed pedigree analysis under different inheritance patterns according to American College of Medical Genetics guidelines. Results were confirmed by Sanger sequencing. RESULTS: Two novel loss-of-function indels (c.5027_5028insTGTCCTCC, p.D1677Vfs*8; c.5856delG, p.S1953Lfs*27) and one nonsense variant (c.8034C>A, p.Y2678*) of FBN1 were identified in Family 1, Family 2 and Family 3, respectively. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of FBN1 were located in the cbEGF region and a conserved domain across species and were not reported previously. CONCLUSIONS: Our study extended and strengthened the vital role of FBN1 LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation-based pre- and postnatal screening, genetic diagnosis and clinical management for MFS. PeerJ Inc. 2018-11-13 /pmc/articles/PMC6238762/ /pubmed/30479897 http://dx.doi.org/10.7717/peerj.5927 Text en © 2018 Pu et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Genetics
Pu, Zhening
Sun, Haoliang
Du, Junjie
Cheng, Yue
He, Keshuai
Ni, Buqing
Gu, Weidong
Dai, Juncheng
Shao, Yongfeng
Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome
title Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome
title_full Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome
title_fullStr Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome
title_full_unstemmed Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome
title_short Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome
title_sort family-based whole-exome sequencing identifies novel loss-of-function mutations of fbn1 for marfan syndrome
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238762/
https://www.ncbi.nlm.nih.gov/pubmed/30479897
http://dx.doi.org/10.7717/peerj.5927
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