Key result
Targeted sequencing identifies a novel FBN1 variant causing sporadic Marfan syndrome via alternative splicing.
Why the study?
Although FBN1 mutations are the most common cause of Marfanoid habitus, about 10% of Marfan syndrome patients remain unaware of their specific genetic defects.
Case Report (n=1)
No
This case highlights the importance of functional investigations for intronic variants in gene panels to identify pathogenic alternative splicing in Marfan syndrome.
Expands recognized FBN1 intronic variants in MFS; leaves open whether splicing analysis should enter routine diagnostic panels.
Marfan syndrome (MFS) is a hereditary connective tissue disease whose clinical severity varies widely. Mutations of the FBN1 gene encoding fibrillin-1 are the most common genetic cause of Marfanoid habitus; however, about 10% of MFS patients are unaware of their genetic defects. Herein, we report a Korean patient with MFS and annuloaortic ectasia caused by an intronic c.5225-3C>G variant of the FBN1 gene identified by targeted panel sequencing. The reverse transcription analysis of FBN1 revealed that the intron 43 sequence from positions c.5297-1516 to c.5297-1 was retained at the coding sequence as a consequence of the c.5225-3C>G variant enhancing a cryptic splice acceptor site (c.5297-1518_5297-1517AG) in intron 43. The retained sequence of the part of intron 43 caused the same effect as insertion mutation (NM_000138.5:c.5297_c.5298ins5297-1516_5297-1), resulting in a frameshift mutation resulting in p.Ile1767Trpfs*3. The patient underwent an urgent modified Bentall operation with a 29 mm mechanical valve for annuloaortic ectasia and severe aortic valve regurgitation. This report emphasizes the need for functional investigations into the diagnostic workflows of certain diseases or gene panels with suspected high rates of intronic variants and potential pathogenic effects. Hence, further descriptions of individuals with intronic variants causing alternative splicing expected to have pathogenic effects at different transcript levels are crucial for improving our understanding.
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Kim et al. (2022) conducted a case report in Marfan syndrome (n=1). FBN1 c.5225-3C>G variant vs. Unaffected family members (wild-type) was evaluated on Pathogenicity of the FBN1 variant. Targeted panel sequencing identified a novel de novo intronic c.5225-3C>G variant in the FBN1 gene that causes alternative splicing and sporadic Marfan syndrome with annuloaortic ectasia.
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