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Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that canonically affects the ocular, skeletal, and cardiovascular system, in which aortic tear and rupture is the leading cause of death for MFS patients. Genetically, MFS is primarily associated with fibrillin-1 (FBN1) pathog...

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Autores principales: Hu, Kui, Wan, Yun, Lee, Fu-Tsuen, Chen, Jinmiao, Wang, Hao, Qu, Haonan, Chen, Tao, Lu, Wang, Jiang, Zhenwei, Gao, Lufang, Ji, Xiaojuan, Sun, Liqun, Xiang, Daokang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081721/
https://www.ncbi.nlm.nih.gov/pubmed/35547258
http://dx.doi.org/10.3389/fgene.2022.857095
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author Hu, Kui
Wan, Yun
Lee, Fu-Tsuen
Chen, Jinmiao
Wang, Hao
Qu, Haonan
Chen, Tao
Lu, Wang
Jiang, Zhenwei
Gao, Lufang
Ji, Xiaojuan
Sun, Liqun
Xiang, Daokang
author_facet Hu, Kui
Wan, Yun
Lee, Fu-Tsuen
Chen, Jinmiao
Wang, Hao
Qu, Haonan
Chen, Tao
Lu, Wang
Jiang, Zhenwei
Gao, Lufang
Ji, Xiaojuan
Sun, Liqun
Xiang, Daokang
author_sort Hu, Kui
collection PubMed
description Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that canonically affects the ocular, skeletal, and cardiovascular system, in which aortic tear and rupture is the leading cause of death for MFS patients. Genetically, MFS is primarily associated with fibrillin-1 (FBN1) pathogenic variants. However, the disease-causing variant in approximately 10% of patients cannot be identified, partly due to some cryptic mutations that may be missed using routine exonic sequencing, such as non-coding intronic variants that affects the RNA splicing process. We present a 32-year female with typical MFS systemic presentation that reached to a clinical diagnosis according to the revised Ghent nosology. We performed whole-exome sequencing (WES) but the report failed to identify known causal variants when analyzing the exonic sequence. However, further investigation on the exon/intron boundaries of the WES report revealed a candidate intronic variant of the fibrillin 1 (FBN1) gene (c.248-3 C>G) that predicted to affect the RNA splicing process. We conducted minigene splicing analyses and demonstrated that the c.248-3 C>G variant abolished the canonical splicing site of intron 3, leading to activation of two cryptic splicing sites and causing insertion (c.248-1_248-2insAG and c.248-1_248-282ins). Our study not only characterizes an intronic variant to the mutational spectrum of the FBN1 gene in MFS and its aberrant effect on splicing, but highlights the importance to not neglect the exon/intron boundaries when reporting and assessing WES results. We point out the need of conducting functional analysis to verify the pathogenicity of intronic mutation, and the opportunity to re-consider the standard diagnostic approaches in cases of clinically diagnosed MFS with normal or variant of unknown significance genetic results.
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spelling pubmed-90817212022-05-10 Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome Hu, Kui Wan, Yun Lee, Fu-Tsuen Chen, Jinmiao Wang, Hao Qu, Haonan Chen, Tao Lu, Wang Jiang, Zhenwei Gao, Lufang Ji, Xiaojuan Sun, Liqun Xiang, Daokang Front Genet Genetics Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that canonically affects the ocular, skeletal, and cardiovascular system, in which aortic tear and rupture is the leading cause of death for MFS patients. Genetically, MFS is primarily associated with fibrillin-1 (FBN1) pathogenic variants. However, the disease-causing variant in approximately 10% of patients cannot be identified, partly due to some cryptic mutations that may be missed using routine exonic sequencing, such as non-coding intronic variants that affects the RNA splicing process. We present a 32-year female with typical MFS systemic presentation that reached to a clinical diagnosis according to the revised Ghent nosology. We performed whole-exome sequencing (WES) but the report failed to identify known causal variants when analyzing the exonic sequence. However, further investigation on the exon/intron boundaries of the WES report revealed a candidate intronic variant of the fibrillin 1 (FBN1) gene (c.248-3 C>G) that predicted to affect the RNA splicing process. We conducted minigene splicing analyses and demonstrated that the c.248-3 C>G variant abolished the canonical splicing site of intron 3, leading to activation of two cryptic splicing sites and causing insertion (c.248-1_248-2insAG and c.248-1_248-282ins). Our study not only characterizes an intronic variant to the mutational spectrum of the FBN1 gene in MFS and its aberrant effect on splicing, but highlights the importance to not neglect the exon/intron boundaries when reporting and assessing WES results. We point out the need of conducting functional analysis to verify the pathogenicity of intronic mutation, and the opportunity to re-consider the standard diagnostic approaches in cases of clinically diagnosed MFS with normal or variant of unknown significance genetic results. Frontiers Media S.A. 2022-04-25 /pmc/articles/PMC9081721/ /pubmed/35547258 http://dx.doi.org/10.3389/fgene.2022.857095 Text en Copyright © 2022 Hu, Wan, Lee, Chen, Wang, Qu, Chen, Lu, Jiang, Gao, Ji, Sun and Xiang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Hu, Kui
Wan, Yun
Lee, Fu-Tsuen
Chen, Jinmiao
Wang, Hao
Qu, Haonan
Chen, Tao
Lu, Wang
Jiang, Zhenwei
Gao, Lufang
Ji, Xiaojuan
Sun, Liqun
Xiang, Daokang
Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome
title Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome
title_full Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome
title_fullStr Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome
title_full_unstemmed Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome
title_short Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome
title_sort functional analysis of an intronic fbn1 pathogenic gene variant in a family with marfan syndrome
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081721/
https://www.ncbi.nlm.nih.gov/pubmed/35547258
http://dx.doi.org/10.3389/fgene.2022.857095
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