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

Elisabeth Gillis, Marlies Kempers, Simone Salemink, Janneke Timmermans, Emile C. Cheriex, Sebastiaan C. A. M. Bekkers, Erik Fransen, Christine E. M. De Die-Smulders, Bart L. Loeys*, Lut Van Laer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)571-574
JournalHuman Mutation
Issue number5
Publication statusPublished - May 2014


  • Marfan syndrome
  • deep intronic mutation
  • FBN1
  • pseudo-exon

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