An FBN1 deep intronic mutation in a familial case of Marfan syndrome: an explanation for genetically unsolved cases?

Hum Mutat. 2014 May;35(5):571-4. doi: 10.1002/humu.22540. Epub 2014 Apr 7.


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 DNA FBN1 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.

Keywords: FBN1; Marfan syndrome; deep intronic mutation; pseudo-exon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Child, Preschool
  • Exons
  • Fibrillin-1
  • Fibrillins
  • Humans
  • Introns
  • Male
  • Marfan Syndrome / genetics*
  • Marfan Syndrome / pathology
  • Microfilament Proteins / genetics*
  • Middle Aged
  • Pedigree
  • Point Mutation*


  • FBN1 protein, human
  • Fibrillin-1
  • Fibrillins
  • Microfilament Proteins