An FBN1 Deep Intronic Mutation in a Familial Case of Marfan Syndrome: An Explanation for Genetically Unsolved Cases?

Marfan syndrome (MFS) is caused by mutations in the FBN1 (fibrillin-1) gene, but approximately 10% of MFS cases remain genetically unsolved. Here, we report a new FBN1 mutation in an MFS family that had remained negative after extensive molecular genomic DNAFBN1 testing, including denaturing high-performance liquid chromatography, Sanger sequencing, and multiplex ligation-dependent probe amplification. Linkage analysis in the family and cDNA sequencing of the proband revealed a deep intronic point mutation in intron 56 generating a new splice donor site. This mutation results in the integration of a 90-bp pseudo-exon between exons 56 and 57 containing a stop codon, causing nonsense-mediated mRNA decay. Although more than 90% of FBN1 mutations can be identified with regular molecular testing at the genomic level, deep intronic mutations will be missed and require cDNA sequencing or whole-genome sequencing.