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Published on: August 15, 2019
A Novel Heterozygous Intronic FBN1 Variant Contributes to Aberrant RNA Splicing in Marfan Syndrome
Djouhayna Dougarem1, Yi-Xiao Chen1, Yi-Na Sun1
1School of Medicine, Zhejiang University, Hangzhou, China.
Background:
Marfan syndrome (MFS) is a complex genetic systemic connective tissue disorder. It is well known that genetic factors play a critical role in the progression of MFS, with nearly all cases attributed to variants in the FBN1 gene.
Methods:
We investigated a Chinese family with MFS spanning two generations. Whole exome sequencing, in silico analysis, minigene constructs, transfection, RT-PCR, and protein secondary structure analysis were used to analyze the genotype of the proband and his father.
Results:
The main clinical manifestations of the proband and his father were subluxation of the left lens and high myopia with pectus deformity. Whole exome sequencing identified a novel single nucleotide variant (SNV) in the FBN1 gene at a non-canonical splice site, c.443-3C>G. This variant resulted in two abnormal mRNA transcripts, leading to a frameshift and an in-frame insertion. Further in vitro experiments indicated that the c.443-3C>G variant in FBN1 was pathogenic and functionally harmful.
Conclusion:
This research identified a novel intronic pathogenic FBN1: c.443-3C>G gene variant, which led to two different aberrant splicing effects. Further functional analysis expands the variant spectrum and provides a strong indication and sufficient basis for preimplantation genetic testing for monogenic disease (PGT-M).
Insights
A novel FBN1 gene variant, c.443-3C>G, was identified in a Chinese family with Marfan syndrome (MFS). This pathogenic variant causes aberrant splicing, impacting connective tissue and supporting genetic testing for MFS.
Area of Science:
- Genetics
- Molecular Biology
- Medical Science
Background:
- Marfan syndrome (MFS) is a genetic disorder affecting connective tissue.
- Mutations in the FBN1 gene are the primary cause of MFS.
Purpose of the Study:
- To investigate the genetic basis of MFS in a Chinese family.
- To identify and characterize novel pathogenic variants in the FBN1 gene.
Main Methods:
- Whole exome sequencing was performed on affected individuals.
- In silico analysis, minigene assays, and RT-PCR were used to assess variant effects.
- Protein secondary structure analysis was conducted.
Main Results:
- A novel intronic FBN1 variant, c.443-3C>G, was identified in a Chinese family with MFS.
- This variant led to two distinct aberrant mRNA splicing events (frameshift and in-frame insertion).
- In vitro experiments confirmed the pathogenic and functional impact of the c.443-3C>G variant.
Conclusions:
- The study identified a novel pathogenic FBN1 variant (c.443-3C>G) causing Marfan syndrome through aberrant splicing.
- This finding expands the known spectrum of FBN1 variants.
- The results provide a basis for preimplantation genetic testing for monogenic disease (PGT-M).
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