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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.857095/full |
| _version_ | 1818523978260545536 |
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| author | Kui Hu Yun Wan Fu-Tsuen Lee Fu-Tsuen Lee Jinmiao Chen Hao Wang Haonan Qu Tao Chen Wang Lu Zhenwei Jiang Lufang Gao Xiaojuan Ji Liqun Sun Daokang Xiang |
| author_facet | Kui Hu Yun Wan Fu-Tsuen Lee Fu-Tsuen Lee Jinmiao Chen Hao Wang Haonan Qu Tao Chen Wang Lu Zhenwei Jiang Lufang Gao Xiaojuan Ji Liqun Sun Daokang Xiang |
| author_sort | Kui Hu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-11T05:51:23Z |
| format | Article |
| id | doaj.art-52a895243a0140dc9489db42c77069a5 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-11T05:51:23Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-52a895243a0140dc9489db42c77069a52022-12-22T01:18:49ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-04-011310.3389/fgene.2022.857095857095Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan SyndromeKui Hu0Yun Wan1Fu-Tsuen Lee2Fu-Tsuen Lee3Jinmiao Chen4Hao Wang5Haonan Qu6Tao Chen7Wang Lu8Zhenwei Jiang9Lufang Gao10Xiaojuan Ji11Liqun Sun12Daokang Xiang13Department of Cardiovascular Surgery, Guizhou Provincial People’s Hospital, Guiyang, ChinaDepartment of Endocrinology, Guizhou Provincial People’s Hospital, Guiyang, ChinaDepartment of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, CanadaDivision of Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, CanadaDepartment of Cardiovascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, ChinaInstitute of Precision Medicine, The Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Thoracic and Cardiovascular Surgery, The Third People’s Hospital of Mianyang City, Mianyang, ChinaDepartment of Cardiovascular Surgery, Guizhou Provincial People’s Hospital, Guiyang, ChinaDepartment of Cardiovascular Surgery, Guizhou Provincial People’s Hospital, Guiyang, ChinaDepartment of Cardiovascular Surgery, Guizhou Provincial People’s Hospital, Guiyang, ChinaDepartment of Cardiovascular Surgery, Guizhou Provincial People’s Hospital, Guiyang, ChinaDepartment of Ultrasound, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, ChinaDivision of Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, CanadaDepartment of Cardiovascular Surgery, Guizhou Provincial People’s Hospital, Guiyang, ChinaMarfan 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.https://www.frontiersin.org/articles/10.3389/fgene.2022.857095/fullMarfan syndromeintronic variantfibrillin 1RNA splicinggenetic analysis |
| spellingShingle | Kui Hu Yun Wan Fu-Tsuen Lee Fu-Tsuen Lee Jinmiao Chen Hao Wang Haonan Qu Tao Chen Wang Lu Zhenwei Jiang Lufang Gao Xiaojuan Ji Liqun Sun Daokang Xiang Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome Frontiers in Genetics Marfan syndrome intronic variant fibrillin 1 RNA splicing genetic analysis |
| 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 | Marfan syndrome intronic variant fibrillin 1 RNA splicing genetic analysis |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.857095/full |
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